U.S. patent application number 16/418754 was filed with the patent office on 2019-09-05 for methods of treating pediatric patients using dexmedetomidine.
This patent application is currently assigned to Hospira, Inc.. The applicant listed for this patent is Hospira, Inc.. Invention is credited to Marcelo Garcia da Rocha, Edward Koo, Dennis James Stalker, Wayne Wisemandle.
Application Number | 20190269657 16/418754 |
Document ID | / |
Family ID | 47226666 |
Filed Date | 2019-09-05 |
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United States Patent
Application |
20190269657 |
Kind Code |
A1 |
Garcia da Rocha; Marcelo ;
et al. |
September 5, 2019 |
METHODS OF TREATING PEDIATRIC PATIENTS USING DEXMEDETOMIDINE
Abstract
The presently disclosed subject matter relates to methods of
administering an effective amount of dexmedetomidine to a pediatric
patient in order to reduce the incidence of neurological damage.
More particularly, the presently disclosed subject matter relates
to methods of providing sedation or analgesia to a pediatric
patient by administering a dexmedetomidine infusion and optionally
a loading dose. The dexmedetomidine can be administered before,
during, or after surgery.
Inventors: |
Garcia da Rocha; Marcelo;
(Vernon Hills, IL) ; Wisemandle; Wayne; (Gurnee,
IL) ; Stalker; Dennis James; (Vernon Hills, IL)
; Koo; Edward; (Vernon Hills, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hospira, Inc. |
Lake Forest |
IL |
US |
|
|
Assignee: |
Hospira, Inc.
Lake Forest
IL
|
Family ID: |
47226666 |
Appl. No.: |
16/418754 |
Filed: |
May 21, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13343693 |
Jan 4, 2012 |
|
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16418754 |
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61547626 |
Oct 14, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4164 20130101;
A61K 31/4174 20130101; A61P 25/20 20180101 |
International
Class: |
A61K 31/4174 20060101
A61K031/4174; A61K 31/4164 20060101 A61K031/4164; A61P 25/20
20060101 A61P025/20 |
Claims
1. A method of providing sedation in a pediatric patient in need
thereof, wherein the method comprises administering a
pharmaceutical composition comprising dexmedetomidine or a
pharmaceutically acceptable salt thereof at a concentration of
between about 0.005 to about 50 .mu.g/mL to the pediatric patient;
wherein the dexmedetomidine or a pharmaceutically acceptable salt
thereof is administered as a continuous infusion at a concentration
of between about 0.005 .mu.g/kg/hr to about 1.5 .mu.g/kg/hr; and
wherein the pediatric patient is less than about 17 years of
age.
2. The method of claim 1, wherein the dexmedetomidine is
administered at a concentration of between about 0.005 .mu.g/kg/hr
to about 1 .mu.g/kg/hr.
3. The method of claim 2, wherein the dexmedetomidine is
administered at a concentration of about 0.2 .mu.g/kg/hr.
4. The method of claim 1, wherein the dexmedetomidine is
administered for a period of time of less than about 36 hours.
5. The method of claim 4, wherein the dexmedetomidine is
administered for a period of time of less than about 24 hours.
6. The method of claim 1, wherein the dexmedetomidine is
administered by an intravenous infusion.
7. The method of claim 1, wherein the dexmedetomidine is
parenterally administered.
8. The method of claim 1, wherein the dexmedetomidine is
administered to the pediatric patient in an intensive care
unit.
9. The method of claim 1, wherein the pharmaceutical composition
comprises dexmedetomidine or a pharmaceutically acceptable salt
thereof at a concentration of between about 0.005 to about 5
.mu.g/mL.
10. The method of claim 9, wherein the pharmaceutical composition
comprises dexmedetomidine or a pharmaceutically acceptable salt
thereof at a concentration of about 4 .mu.g/mL.
11. The method of claim 1, wherein the pediatric patient is
critically ill.
12. The method of claim 1, wherein the pediatric patient is
intubated.
13. The method of claim 12, wherein the pediatric patient is
intubated prior to, during, or after administration of the
dexmedetomidine.
14. The method of claim 1, wherein the dexmedetomidine is
administered as a single continuous dose.
15. The method of claim 1, wherein the pediatric patient is less
than about 6 years of age.
Description
1. CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/343,693 filed Jan. 4, 2012, which claims priority under 35
U.S.C. .sctn. 119 to U.S. Provisional Application Ser. No.
61/547,626 filed Oct. 14, 2011, both of which are hereby
incorporated by reference in their entireties, and to both of which
priority is claimed.
2. FIELD OF THE INVENTION
[0002] The presently disclosed subject matter relates to a method
of providing a safe and effective sedative and/or analgesic agent
for pediatric patients. More particularly, the presently disclosed
subject matter relates to reducing, preventing, and/or ameliorating
neurological damage in a pediatric patient by administering
dexmedetomidine.
3. BACKGROUND OF THE INVENTION
[0003] Sedation is an important component of care for pediatric
patients in the intensive care unit (ICU) not only for their
physiologic well being, but also for patient safety and the safety
of the caregivers.
[0004] Benzodiazepines and opioids, such as fentanyl or morphine,
are frequently administered to provide sedation and analgesia in
the pediatric intensive care unit (PICU). Propofol has been shown
to cause severe, life-threatening metabolic alterations in children
including circulatory failure, and is not indicated in the
pediatric population for continuous intensive care sedation. (See
Propofol Injectable Emulsion [package insert]. Lake Forest Ill.:
Hospira, Inc.: 2008). With prolonged administration of
benzodiazepines and opioids, tolerance and physical dependence may
develop. Midazolam sedation in some pediatric patients causes
oversedation alternating with under sedation and paradoxical
agitation. (See Midazolam hydrochloride [Package Insert]. Lake
Forest, Ill.: Hospira, Inc.: 2005).
[0005] Recent reports of apoptosis and neurodevelopment
abnormalities in neonatal and infant animal models from gamma-amino
butyric acid (GABA)-agonist drugs have heightened the concern of
sedating neonates and infants with benzodiazepines. (See Young et
al. Brit J Pharma 2005; 146:189-197; and Sander et al. Brit J
Anaesth 2008; 101 (5): 597-609). The concomitant administration of
opioids further complicates pediatric patient management because of
respiratory depression. Therefore, there is a significant unmet
need for safe and effective sedation and analgesia in pediatric
patients.
[0006] Dexmedetomidine (Precedex.RTM.) is a highly selective
alpha-2 adrenergic agonist with significant sedative, analgesic,
and anxiolytic effects. Dexmedetomidine is currently approved by
the FDA for sedation of initially intubated and mechanically
ventilated adult patients in an intensive care setting, and is also
approved for sedation of non-intubated adult patients as a
component of monitored anesthesia care during surgical or
diagnostic procedures. Dexmedetomidine is the only sedative
approved in the United States for administration as a continuous
infusion in non-intubated ICU patients because it does not
significantly affect respiratory drive.
[0007] Sedation with dexmedetomidine for adult patients in the ICU
has been widely studied. When used in combination with opioids or
benzodiazepines, dexmedetomidine often allows for a reduction in
the doses of the other agents, reducing the risk of respiratory
depression.
4. SUMMARY OF THE INVENTION
[0008] The present invention is directed to methods of sedation or
analgesia in a pediatric patient in need thereof comprising
administering dexmedetomidine to the patient, wherein the
dexmedetomidine is administered in an amount effective to reduce
the incidence of neurological damage.
[0009] In one embodiment, the dexmedetomidine is administered at a
concentration of between about 0.01 to about 2.5 .mu.g/kg/hr, the
pediatric is about 17 years of age or younger, the dexmedetomidine
is administered as a continuous infusion for a period of time of
less than about 36 hours, and the dexmedetomidine is administered
in an amount effective to reduce the incidence of neurological
damage.
[0010] In a particular embodiment, the pediatric patient is a
preterm neonate. In one embodiment, the pediatric patient's
gestational age ranges from about 7 months to about 11 months.
[0011] In certain embodiments, the pediatric patient is intubated
prior to, during, or after administration of the dexmedetomidine.
In one embodiment, the pediatric patient is critically ill.
[0012] In particular embodiments, the dexmedetomidine is
parenterally administered. In certain embodiments, the
dexmedetomidine is administered by an intravenous infusion.
[0013] In particular embodiments, the neurological damage is
cellular degeneration or neuroapoptosis. In one embodiment, the
neurological damage occurs in a cortex lamina layer selected from
the group consisting of layer I and layer II.
[0014] In certain embodiments, the dexmedetomidine is administered
before surgery. In particular embodiments, the dexmedetomidine is
administered after surgery. In a specific embodiment, the
dexmedetomidine is administered after cardiopulmonary bypass. In
one embodiment, the pediatric patient has an age selected from the
group consisting of between about 12 to about 17 years of age and
about 2 years of age or younger.
[0015] In particular embodiments, the administration of
dexmedetomidine reduces a need for rescue medication. In one
embodiment, the rescue medication is a sedative. In a specific
embodiment, the rescue medication is an analgesic.
[0016] In certain embodiments, the administration of
dexmedetomidine further comprises a first loading dose prior to a
maintenance dose and wherein the loading dose ranges from about 0
to about 0.4 .mu.g/kg. In one embodiment, no loading dose is
administered.
5. DESCRIPTION OF THE FIGURES
[0017] FIG. 1 depicts the mean plasma concentration of
dexmedetomidine over time for the full evaluable population in
Example 3.
[0018] FIG. 2 depicts the plasma clearance over age for the full
evaluable population in Example 3.
[0019] FIG. 3 depicts the plasma clearance over weight for the full
evaluable population in Example 3.
[0020] FIG. 4 depicts the weight-adjusted plasma clearance versus
age for the full evaluable population in Example 3.
[0021] FIG. 5 depicts the weight-adjusted volume of distribution
versus age for the full evaluable population in Example 3.
[0022] FIG. 6 depicts the predicted mean curves for
AUC.sub.0-.infin. generated using the power fit model for Example
3.
[0023] FIG. 7 depicts the predicted mean curves for AUC.sub.0-t
generated using the power fit model for Example 3.
[0024] FIG. 8 depicts the predicted mean curves for C.sub.max
generated using the power fit model for Example 3.
[0025] FIG. 9 depicts the predicted mean curves for C.sub.ss
generated using the power fit model for Example 3.
[0026] FIG. 10 depicts the average Ramsay Sedation Score (RSS)
versus AUC.sub.0-.infin. for the full evaluable population.
[0027] FIG. 11 depicts the average Ramsay Sedation Score (RSS)
versus C.sub.ss for the full evaluable population.
[0028] FIG. 12 depicts representative photomicrographs of TUNEL
staining of the frontal cortex of neonatal monkeys at 5.times. and
10.times. magnification.
[0029] FIG. 13 depicts representative photomicrographs of activated
caspase 3 staining of the frontal cortex of neonatal monkeys at
5.times. and 10.times. magnification.
[0030] FIG. 14 depicts representative photomicrographs of activated
caspase 3 staining of the frontal cortex of neonatal monkeys at
20.times. magnification.
[0031] FIG. 15 depicts representative photomicrographs of the
silver staining of the frontal cortex of neonatal monkeys at
20.times. magnification.
[0032] FIGS. 16A-C depict lineplots of plasma dexmedetomidine
concentrations versus time since the start of the loading dose
infusion for each treatment group for the treatment groups in the
studies of Examples 1, 3, and 5.
[0033] FIGS. 17A-C depicts lineplots of dexmedetomidine
concentrations versus time since the end of the maintenance
infusion are shown for each treatment group for the treatment
groups in the studies of Examples 1, 3, and 5.
[0034] FIGS. 18A-B depict a semilogarithmic scatterplot of
dose-normalized dexmedetomidine plasma concentrations versus time
since the end of the maintenance infusion for the studies of
Examples 1, 3, and 5.
[0035] FIGS. 19A-B depict goodness-of-fit plots for the individual
predicted dexmedetomidine Cp base structural model for the pooled
dataset of Examples 1, 3, and 5.
[0036] FIG. 20 depicts the 90% prediction interval, derived from
the 1000 simulated datasets, overlaid on the observed
dexmedetomidine concentrations versus time since the end of the
maintenance infusion of Examples 1, 3, and 5.
[0037] FIG. 21 depicts a comparison of the 5th, 50th, and 95th
percentile of the prediction-corrected observed and model-based
simulated data of Examples 1, 3, and 5.
[0038] FIGS. 22A-D depicts goodness-of-fit plots for the final
population pharmacokinetics model for the entire population for the
data of Examples 1, 3, and 5.
[0039] FIG. 23 in the upper panel depicts the geometric means and
95% confidence intervals for the individual Bayesian estimates of
dexmedetomidine clearance plotted at the midpoint of each age
group. The lower panels depict the corresponding weight-adjusted
estimates for dexmedetomidine clearance. A line for the population
model-based typical value of each parameter versus age is overlaid
in each plot.
[0040] FIG. 24 in the upper panel depicts the geometric means and
95% confidence intervals for the individual Bayesian estimates of
dexmedetomidine volume of distribution plotted at the midpoint of
each age group. The lower panels depict the corresponding
weight-adjusted estimates for dexmedetomidine volume of
distribution. A line for the population model-based typical value
of each parameter versus age is overlaid in each plot.
[0041] FIG. 25 depicts the pairwise scatterplots of interindividual
variance terms from the final model in Example 6.
[0042] FIG. 26 depicts the 95% confidence intervals for the
individual Bayesian estimates expressed as the percent of the
geometric mean of dexmedetomidine weight-adjusted CL for each age
group as determined from the analysis performed in Example 6.
[0043] FIG. 27 depicts the 95% confidence intervals for the
individual Bayesian estimates expressed as the percent of the
geometric mean of dexmedetomidine weight-adjusted volume of
distribution for each age group as determined from the analysis
performed in Example 6.
[0044] FIG. 28 depicts the 95% confidence intervals for the
individual Bayesian estimates expressed as the percent of the
geometric mean of dexmedetomidine weight-adjusted CL for each age
group as determined from the analysis performed in Example 8.
[0045] FIG. 29 depicts the 95% confidence intervals for the
individual Bayesian estimates expressed as the percent of the
geometric mean of dexmedetomidine weight-adjusted volume of
distribution for each age group as determined from the analysis
performed in Example 8.
[0046] FIGS. 30A-H depict the goodness-of-fit plots for the final
population pharmacokinetic model for dexmedetomidine of Example
8.
[0047] FIGS. 31A-B depict the prediction-corrected visual
predictive check results for the dexmedetomidine concentration
versus time since end of IV.
[0048] FIG. 32 depicts the geometric means and 95% confidence
intervals for the Bayesian estimates of dexmedetomidine clearance
and weight-adjusted clearance in specified age groups with the
population model-based typical values of clearance and
weight-adjusted clearance overlaid.
[0049] FIG. 33 depicts the geometric means and 95% confidence
intervals for the Bayesian estimates of dexmedetomidine volume
distribution and weight-adjusted volume of distribution in
specified age groups, with the population model-based typical
values of volume of distribution and weight-adjusted volume of
distribution overlaid.
[0050] FIGS. 34A-C depict the predicted mean curve for
AUC.sub.0-inf, AUC.sub.0-t, and C.sub.max generated using the power
fit model.
[0051] FIG. 35 depicts a linear plot illustrating the mean
dexmedetomidine concentrations over time. Time Point: 1=pre-dose,
2=end of bolus, 3=30 minutes after start of infusion, 4=60 minutes
after start of infusion, 5=2 hours after start of infusion, 6=4 to
6 hours after start of infusion, 7=6 hours after start of infusion,
8=12 hours after start of infusion, 8.1=23 hours after start of
infusion, 9=30 to 15 minutes prior to end of infusion, 10=end of
infusion, 11=15 minutes after end of infusion, 12=30 minutes after
end of infusion, 13=60 minutes after end of infusion, 14=2 hours
after end of infusion, 15=4 hours after end of infusion, 16=8 hours
after end of infusion, 17=12 hours after end of infusion, 18=15 to
18 hours after end of infusion, 19=24 hours after end of
infusion.
[0052] FIGS. 36A-B depict the clearance and weight-adjusted
clearance over age.
6. DETAILED DESCRIPTION OF THE INVENTION
[0053] The present invention is directed to methods of sedation or
analgesia in a pediatric patient in need thereof comprising
administration of dexmedetomidine to the patient, wherein the
dexmedetomidine is administered in an amount effective to reduce
the incidence of neurological damage.
[0054] For clarity and not by way of limitation, this detailed
description is divided into the following sub-portions:
[0055] 6.1 Definitions;
[0056] 6.2 Pharmaceutical formulations;
[0057] 6.3 Patient populations; and
[0058] 6.4 Methods of treatment.
6.1 Definitions
[0059] The terms used in this specification generally have their
ordinary meanings in the art, within the context of this invention
and in the specific context where each term is used. Certain terms
are discussed below, or elsewhere in the specification, to provide
additional guidance to the practitioner in describing the
compositions and methods of the invention and how to make and use
them.
[0060] According to the present invention, the term
"dexmedetomidine" as used herein refers to a substantially pure,
optically active dextrorotary stereoisomer of medetomidine, as the
free base or pharmaceutically acceptable salt. In one, non-limiting
embodiment, dexmedetomidine has the formula
(S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole. A
pharmaceutically acceptable salt of dexmedetomidine can include
inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid and the like, and
organic acids such as acetic acid, propionic acid, glycolic acid,
pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid,
maleic acid, fumaric acid, tartaric acid, citric acid, benzoic
acid, cinnamic acid, mandelic acid, methanesulfonic acid,
ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.
Preferably, the dexmedetomidine salt is dexmedetomidine HCl. In
other non-limiting embodiments, dexmedetomidine comprises the
structure depicted below in Formula I:
##STR00001##
[0061] The term "pharmaceutical composition" as used in accordance
with the present invention relates to compositions that can be
formulated in any conventional manner using one or more
pharmaceutically acceptable carriers or excipients. A
"pharmaceutically acceptable" carrier or excipient, as used herein,
means approved by a regulatory agency of the Federal or a state
government, or as listed in the U.S. Pharmacopoeia or other
generally recognized pharmacopoeia for use in mammals, and more
particularly in humans.
[0062] The term "dosage" is intended to encompass a formulation
expressed in terms of .mu.g/kg/hr, .mu.g/kg/day, mg/kg/day, or
mg/kg/hr. The dosage is the amount of an ingredient administered in
accordance with a particular dosage regimen. A "dose" is an amount
of an agent administered to a mammal in a unit volume or mass,
e.g., an absolute unit dose expressed in mg of the agent. The dose
depends on the concentration of the agent in the formulation, e.g.,
in moles per liter (M), mass per volume (m/v), or mass per mass
(m/m). The two terms are closely related, as a particular dosage
results from the regimen of administration of a dose or doses of
the formulation. The particular meaning in any case will be
apparent from context.
[0063] The terms "therapeutically effective dose," "effective
amount," and "therapeutically effective amount" refer to the amount
sufficient to produce the desired effect. In some non-limiting
embodiments, a "therapeutically effective dose" means an amount
sufficient to reduce by at least about 15%, preferably by at least
50%, more preferably by at least 90%, and most preferably prevent,
a clinically significant deficit in the activity, function and
response of the host. Alternatively, a therapeutically effective
amount is sufficient to cause an improvement in a clinically
significant condition in the host. These parameters will depend on
the severity of the condition being treated, other actions, such as
diet modification, that are implemented, the weight, age, and sex
of the subject, and other criteria, which can be readily determined
according to standard good medical practice by those of skill in
the art. In other non-limiting embodiments a therapeutic response
may be any response that a user (e.g., a clinician) will recognize
as an effective response to the therapy. Thus, a therapeutic
response will generally be an induction of a desired effect, such
as, for example, sedation or analgesia.
[0064] The terms "intensive care unit" or "ICU" as used herein
refer to any setting that provides intensive care.
[0065] The term "gestational age" as used herein is calculated as
the time elapsed since the first day of the last menstrual period.
If pregnancy was achieved using assisted reproductive technology,
gestational age is calculated by adding two weeks to the
gestational age as calculated above.
[0066] The term "pediatric patient" as used herein means a human
patient that is 17 years old or younger. In certain non-limiting
embodiments, the patient is 16 years old or younger, or 15 years
old or younger, or 14 years old or younger, or 13 years old or
younger, or 12 years old or younger, or 11 years old or younger, or
10 years old or younger, or 9 years old or younger, or 8 years old
or younger, or 7 years old or younger, or 6 years old or younger,
or 5 years old or younger, or 4 years old or younger, or 3 years
old or younger, or 2 years old or younger, or 1 year old or
younger, or 6 months old or younger, or 4 months old or younger, or
2 months old or younger, or 1 months old or younger. In particular
embodiments, the pediatric patient is between about 12 to about 17
years of age. In one embodiment, the pediatric patient has an age
selected from the group consisting of between about 12 to about 17
years of age and about 2 years of age or younger. In one
embodiment, the pediatric patient has exited the womb just prior to
administration of the dexmedetomidine.
[0067] In certain embodiments, the "pediatric patient" is a preterm
neonate. As used herein, the term "preterm neonate" refers to a
child that is born prior to 37 weeks from the start of the last
menstrual period. If pregnancy was achieved using assisted
reproductive technology, a child is a preterm neonate if the child
is calculated by adding two weeks to the age as calculated
above.
[0068] In certain embodiments, the pediatric patient has a
gestational age of between about 20 weeks and about 44 weeks, or
between about 20 weeks and about 40 weeks, or between about 20
weeks and about 38 weeks, or between about 20 weeks and about 36
weeks, or between about 20 weeks and about 34 weeks, or between
about 20 weeks and about 30 weeks, or between about 20 weeks and
about 28 weeks, or between about 20 weeks and about 24 weeks. In
certain embodiments, the pediatric patient has a gestational age of
between about 36 weeks and about 44 weeks, or between about 36
weeks and about 42 weeks, or between about 36 weeks and about 40
weeks, or between about 36 weeks and about 38 weeks.
[0069] As used herein, the term "neurological damage" refers to
various types of neurocognitive, psychocognitive, and/or neuromotor
or motor impairment, or combinations thereof, discussed in further
detail below.
[0070] As used herein, the term "a reduction in the incidence of"
refers to a reduction in the severity of, reduction in the number
of, prevention of, or delay of the development of one or more
incidences thereof, or a combination thereof.
[0071] The term "about" or "approximately" means within an
acceptable error range for the particular value as determined by
one of ordinary skill in the art, which will depend in part on how
the value is measured or determined, i.e., the limitations of the
measurement system. For example, "about" can mean within 3 or more
than 3 standard deviations, per the practice in the art.
Alternatively, "about" can mean a range of up to 20%, preferably up
to 10%, more preferably up to 5%, and more preferably still up to
1% of a given value. Alternatively, particularly with respect to
biological systems or processes, the term can mean within an order
of magnitude, preferably within 5-fold, and more preferably within
2-fold, of a value.
6.2 Pharmaceutical Compositions
[0072] The pharmaceutical compositions of dexmedetomidine suitable
for parenteral administration can be in the form of suspensions,
solutions, or emulsions, in oily or aqueous vehicles, and can
contain formulatory agents such as suspending, stabilizing,
solubilizing, and/or dispersing agents. The form can be sterile and
can be fluid. It can be stable under the conditions of manufacture
and storage and can be preserved against the contaminating action
of microorganisms such as bacteria and fungi. Alternatively, the
dexmedetomidine can be in sterile powder form for reconstitution
with a suitable vehicle before use. The pharmaceutical compositions
can be presented in unit dose form, in ampoules, or other unit-dose
containers, or in multi-dose containers. Alternatively, the
pharmaceutical compositions can be stored in a freeze-dried
(lyophilized) condition requiring only the addition of sterile
liquid carrier, for example, water for injections immediately prior
to use. Extemporaneous injection solutions and suspensions can be
prepared from sterile powders, granules or tablets.
[0073] In some non-limiting embodiments, the dexmedetomidine
composition is formulated as a liquid. In certain non-limiting
embodiments, the dexmedetomidine liquid composition comprises
dexmedetomidine, or a pharmaceutically acceptable salt thereof, at
a concentration of between about 0.005 .mu.g/mL and about 100
.mu.g/mL, or between about 0.005 .mu.g/mL and about 50 .mu.g/mL, or
between about 0.005 .mu.g/mL and about 25 .mu.g/mL, or between
about 0.005 .mu.g/mL and about 15 .mu.g/mL, or between about 0.005
.mu.g/mL and about 10 .mu.g/mL, or between about 0.005 .mu.g/mL and
about 7 .mu.g/mL, or between about 0.005 .mu.g/mL and about 5
.mu.g/mL, or between about 0.005 .mu.g/mL and about 4 .mu.g/mL, or
between about 0.005 .mu.g/mL and about 3 .mu.g/mL, or between about
0.005 .mu.g/mL and about 2 .mu.g/mL, or between about 0.005
.mu.g/mL and about 1 .mu.g/mL, or between about 0.005 .mu.g/mL and
about 0.5 .mu.g/mL, or between about 0.005 .mu.g/mL and about 0.05
.mu.g/mL.
[0074] In certain non-limiting embodiments, the dexmedetomidine
liquid composition comprises dexmedetomidine, or a pharmaceutically
acceptable salt thereof, at a concentration of about 0.5 .mu.g/mL,
or about 1.0 .mu.g/mL, or about 2.0 .mu.g/mL, or about 4.0
.mu.g/mL.
[0075] In one embodiment, the dexmedetomidine composition is a
premixed formulation that does not require reconstitution or
dilution prior to administration to a patient, as disclosed in U.S.
application Ser. No. 13/343,672, filed on Jan. 4, 2012, titled
"Dexmedetomidine Premix Formulation," is hereby incorporated by
reference in its entirety.
[0076] Excipients that are suitable for the dexmedetomidine
composition include preservatives, suspending agents, stabilizers,
dyes, buffers, antibacterial agents, antifungal agents, and
isotonic agents, for example, sugars or sodium chloride. As used
herein, the term "stabilizer" refers to a compound optionally used
in the pharmaceutical compositions of the present invention in
order to avoid the need for sulphite salts and increase storage
life. Non-limiting examples of stabilizers include
antioxidants.
[0077] The pharmaceutical composition can comprise one or more
pharmaceutically acceptable carriers. The carrier can be a solvent
or dispersion medium. Non-limiting examples of pharmaceutically
acceptable carriers include water, saline, ethanol, polyol (e.g.,
glycerol, propylene glycol and liquid polyethylene glycol), oils,
and suitable mixtures thereof.
[0078] The parenteral formulation can be sterilized. Non-limiting
examples of sterilization techniques include filtration through a
bacterial-retaining filter, terminal sterilization, incorporation
of sterilizing agents, irradiation, heating, vacuum drying, and
freeze drying.
6.3 Patient Populations
[0079] The presently disclosed subject matter comprises
administering dexmedetomidine to a pediatric patient. In certain
embodiments, the pediatric patient is intubated. The pediatric
patient can be intubated prior to, during, or after administration
of the dexmedetomidine. The pediatric patient can be intubated by
the nasotracheal, endotracheal, direct oral laryngoscopy or by
fibreoptic routes, or via tracheotomy.
[0080] In particular embodiments, the patient is critically ill. In
one embodiment, the pediatric patient suffers from one or more
medical conditions. In certain embodiments, the medical condition
is a lung disorder, brain disorder, heart disorder, liver disorder,
kidney disorder, eye or ear disorder, gastrointestinal disorder, or
skin disorder. Non-limiting examples of lung disorders include
respiratory distress syndrome, pneumonia, bronchopulmonary
dysplasia, apnea of prematurity, and pneumothorax. Non-limiting
examples of brain disorders include intraventricular hemorrhage and
cerebral palsy. Non-limiting examples of liver disorders include
jaundice. Non-limiting examples of heart disorders include cardiac
ischemia and patent ductus arteriosus. Non-limiting examples of eye
disorders include retinopathy of prematurity, myopia, and
strabismus. Non-limiting examples of other medical conditions
includes heroin withdrawal, cocaine withdrawal, alcohol fetal
syndrome, HIV-positive status, and Tay Sachs disease.
[0081] In one embodiment, the patient has undergone surgery. The
patient may undergo surgery prior to, during, and/or after
administration of the dexmedetomidine. In certain embodiments, the
dexmedetomidine is administered prior to surgery. In one
embodiment, the dexmedetomidine is administered prior to surgery
for the purpose of reducing an incidence of neurological damage. In
some embodiments, the dexmedetomidine is administered prior to and
during surgery. In particular embodiments, the dexmedetomidine is
administered prior to and after surgery. In certain embodiments,
the dexmedetomidine is administered during and after surgery. In
particular embodiments, the dexmedetomidine is administered prior
to, during, and after surgery.
[0082] Surgery refers to any manual or operative methods or
manipulations for the treatment or prevention of disease, injury or
deformity. Surgery can be performed by a doctor, surgeon or
dentist, generally in a hospital or other health care facility.
Pediatric patients undergoing surgery can be hospitalized or
ambulatory, e.g., out-patient surgery. The surgery can be
conservative (e.g. surgery to preserve or remove with minimal risk,
diseased or injured organs, tissues, or extremities) or radical
(e.g. surgery designed to extirpate all areas of locally extensive
disease and adjacent zones of lymphatic drainage).
[0083] Non-limiting examples of surgery include surgeries performed
on the cardiovascular system, including the heart and blood
vessels; surgeries performed on the musculoskeletal system,
including the bones and muscles; surgeries performed on the
respiratory system, including the trachea and the lungs; surgeries
performed on the integumentary system, including the skin and
nails; surgeries performed on the mediastinum and diaphragm;
surgeries performed on the digestive system, including the
esophagus, stomach, gall bladder and intestines; surgeries
performed on the urinary system, including the kidneys and bladder;
surgeries performed on the male genital system; surgeries performed
on the female genital system; surgeries performed on the endocrine
system, including the pituitary gland, the adrenal glands, and the
endocrine thyroid gland; surgeries performed on the nervous system,
including the brain, spinal cord and peripheral nerves; surgeries
performed on the eye and ocular adnexa; and surgeries performed on
the auditory system.
[0084] Non-limiting examples of surgeries performed on the
cardiovascular system include the repair of congenital heart
defects after birth and heart transplant surgery. Non-limiting
examples of surgeries performed on the musculoskeletal system
include fracture repair, scoliosis surgery and tendon lengthening.
Non-limiting examples of surgeries performed on the respiratory
system include lung transplants, thoracotomy and pneumothorax
surgery. Non-limiting examples of surgeries performed on the
integumentary system include burn treatment and skin grafting.
Non-limiting examples of surgeries performed on the mediastinum and
diaphragm include treatment of congenital diaphragmatic hernia and
removal of mediastinal cysts and tumors. Non-limiting examples of
surgeries performed on the digestive system include intestinal
resection and treatment of pyloric stenosis. Non-limiting examples
of surgeries performed on the urinary system may include kidney
transplants, and treatment of bladder divurticula. Non-limiting
examples of surgeries performed on the male genital system may
include treatment of undescended testes. Non-limiting examples of
surgeries performed on the female genital system may include
ovarian cystectomy. Non-limiting examples of surgeries performed on
the endocrine system may include treatment of hyperparathyroidism.
Non-limiting examples of surgeries performed on the nervous system
may include laminectomy and corpus callosotomy. Non-limiting
examples of surgeries performed on the eye may include strabismus
surgery. Non-limiting examples of surgeries performed on the
auditory system include cochlear implantation. Additional
non-limiting examples of surgery include tonsillectomy, cleft lip
and palate repair, treatment of lymphangioma, tracheoesophageal
fistula repair, neuroblastoma surgery, and treatment of esophageal
atresia. In one embodiment, the patient has undergone
cardiopulmonary bypass.
6.4 Methods of Treatment
[0085] As noted above, the methods of treatment of the invention
are directed to methods of sedation or analgesia in a pediatric
patient comprising administration of dexmedetomidine to the
patient, wherein the dexmedetomidine is administered in an amount
effective to reduce incidence of neurological damage.
[0086] The dexmedetomidine for use in the invention can be
administered via any suitable route, including parenteral,
intravenous, and oral routes. Non-limiting examples of parenteral
routes of administration include intravenous, intramuscular,
subcutaneous, intraperitoneal or intrathecal. Parenteral
administration may be by periodic injections of a bolus of the
preparation, or may be administered by intravenous or
intraperitoneal administration from a reservoir which is external
(e.g., an intravenous bag) or internal (e.g., a bioerodable
implant, a bioartificial organ). See, e.g., U.S. Pat. Nos.
4,407,957 and 5,798,113, each incorporated herein by reference in
their entireties. Intrapulmonary delivery methods and apparatus are
described, for example, in U.S. Pat. Nos. 5,654,007, 5,780,014, and
5,814,607, each incorporated herein by reference in their
entireties. Other useful parenteral delivery systems include
ethylene-vinyl acetate copolymer particles, osmotic pumps,
implantable infusion systems, pump delivery, encapsulated cell
delivery, liposomal delivery, needle-delivered injection,
needle-less injection, nebulizer, aeorosolizer, electroporation,
and transdermal patch. Needle-less injector devices are described
in U.S. Pat. Nos. 5,879,327; 5,520,639; 5,846,233 and 5,704,911,
the specifications of which are herein incorporated herein by
reference in their entireties.
[0087] In yet another non-limiting embodiment, the therapeutic
compound can be delivered in a controlled or sustained release
system. For example, a compound or composition may be administered
using intravenous infusion, continuous infusion, an implantable
osmotic pump, or other modes of administration. In one embodiment,
a pump may be used (see Sefton, 1987, CRC Crit. Ref. Biomed. Eng.
14:201; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989,
N. Engl. J. Med. 321:574). In another embodiment, polymeric
materials can be used (see Langer and Wise eds., 1974, Medical
Applications of Controlled Release, CRC Press: Boca Raton, Fla.;
Smolen and Ball eds., 1984, Controlled Drug Bioavailability, Drug
Product Design and Performance, Wiley, N.Y.; Ranger and Peppas,
1983, J. Macromol. Sci. Rev. Macromol. Chem., 23:61; Levy et al.,
1985, Science 228:190; During et al., 1989, Ann. Neurol., 25:351;
Howard et al., 9189, J.Neurosurg. 71:105). In yet another
embodiment, a controlled release system can be placed in proximity
of the therapeutic target, i.e., the brain, thus requiring only a
fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical
Applications of Controlled Release, Vol. 2, pp. 115-138).
[0088] In certain embodiments, the dexmedetomidine is administered
as a continuous intravenous dose to a pediatric patient at a
concentration of between about 0.005 .mu.g/kg/hr and about 50
.mu.g/kg/hr, or between about 0.005 .mu.g/kg/hr and about 25
.mu.g/kg/hr, or between about 0.005 .mu.g/kg/hr and about 15
.mu.g/kg/hr, or between about 0.005 .mu.g/kg/hr and about 5
.mu.g/kg/hr, or between about 0.005 .mu.g/kg/hr and about 2
.mu.g/kg/hr, or between about 0.005 .mu.g/kg/hr and about 1.5
.mu.g/kg/hr, or between about 0.005 .mu.g/kg/hr and about 1
.mu.g/kg/hr, or between about 0.005 .mu.g/kg/hr and about 0.5
.mu.g/kg/hr, or between about 0.005 .mu.g/kg/hr and about 0.25
.mu.g/kg/hr. In preferred non-limiting embodiments, the
concentration is between about 0.025 .mu.g/kg/hr and about 2.0
.mu.g/kg/hr. In particular embodiments, the dexmedetomidine is
administered as a continuous intravenous dose to a pediatric
patient at a concentration of between about 0.005 .mu.g/kg/hr and
about 50 .mu.g/kg/hr, or between about 0.025 .mu.g/kg/hr and about
50 .mu.g/kg/hr, or between about 0.05 .mu.g/kg/hr and about 50
.mu.g/kg/hr, or between about 0.01 .mu.g/kg/hr and about 50
.mu.g/kg/hr, or between about 0.2 .mu.g/kg/hr and about 50
.mu.g/kg/hr, or between about 0.25 .mu.g/kg/hr and about 50
.mu.g/kg/hr, or between about 0.5 .mu.g/kg/hr and about 50
.mu.g/kg/hr, or between about 0.7 .mu.g/kg/hr and about 50
.mu.g/kg/hr, or between about 1.0 .mu.g/kg/hr and about 50
.mu.g/kg/hr, or between about 1.5 .mu.g/kg/hr and about 50
.mu.g/kg/hr, or between about 2.0 .mu.g/kg/hr and about 50
.mu.g/kg/hr, or between about 5.0 .mu.g/kg/hr and about 50
.mu.g/kg/hr, or between about 10 .mu.g/kg/hr and about 50
.mu.g/kg/hr, or between about 20 .mu.g/kg/hr and about 50
.mu.g/kg/hr.
[0089] In particular embodiments, the dexmedetomidine is
administered as a continuous intravenous dose to a pediatric
patient at a concentration of about 0.01 .mu.g/kg/hr, or about
0.025 .mu.g/kg/hr, or about 0.05 .mu.g/kg/hr, or about 0.1
.mu.g/kg/hr, or about 0.2 .mu.g/kg/hr, or about 0.25 .mu.g/kg/hr,
or about 0.3 .mu.g/kg/hr, or about 0.4 .mu.g/kg/hr, or about 0.5
.mu.g/kg/hr, or about 0.6 .mu.g/kg/hr, or about 0.7 .mu.g/kg/hr, or
about 0.75 .mu.g/kg/hr, or about 0.8 .mu.g/kg/hr, or about 0.9
.mu.g/kg/hr, or about 1.0 .mu.g/kg/hr, or about 1.1 .mu.g/kg/hr, or
about 1.2 .mu.g/kg/hr, or about 1.3 .mu.g/kg/hr, or about 1.4
.mu.g/kg/hr, or about 1.5 .mu.g/kg/hr, or about 1.6 .mu.g/kg/hr, or
about 1.7 .mu.g/kg/hr, or about 1.8 .mu.g/kg/hr, or about 1.9
.mu.g/kg/hr, or about 2.0 .mu.g/kg/hr, or about 2.1 .mu.g/kg/hr, or
about 2.2 .mu.g/kg/hr, or about 2.3 .mu.g/kg/hr, or about 2.4
.mu.g/kg/hr, or about 2.5 .mu.g/kg/hr. In certain embodiments, the
dexmedetomidine is administered as a continuous intravenous dose at
a concentration of about 3.0 .mu.g/kg/hr, or about 3.5 .mu.g/kg/hr,
or about 4.0 .mu.g/kg/hr, or about 4.5 .mu.g/kg/hr, or about 4.0
.mu.g/kg/hr, or about 4.5 .mu.g/kg/hr, or about 5.0 .mu.g/kg/hr, or
about 5.5 .mu.g/kg/hr, about 6.0 .mu.g/kg/hr, or about 6.5
.mu.g/kg/hr, or about 7.0 .mu.g/kg/hr, or about 7.5 .mu.g/kg/hr,
about 8.0 .mu.g/kg/hr, or about 8.5 .mu.g/kg/hr, or about 9.0
.mu.g/kg/hr, or about 9.5 .mu.g/kg/hr, or about 10 .mu.g/kg/hr, or
about 11 .mu.g/kg/hr, or about 12 .mu.g/kg/hr, or about 13
.mu.g/kg/hr, or about 14 .mu.g/kg/hr, or about 15 .mu.g/kg/hr, or
about 16 .mu.g/kg/hr, or about 17 .mu.g/kg/hr, or about 18
.mu.g/kg/hr, or about 19 .mu.g/kg/hr, or about 20 .mu.g/kg/hr, or
about 21 .mu.g/kg/hr, or about 22 .mu.g/kg/hr, or about 23
.mu.g/kg/hr, or about 24 .mu.g/kg/hr, or about 25 .mu.g/kg/hr, or
about 27.5 .mu.g/kg/hr, or about 30 .mu.g/kg/hr, or about 32.5
.mu.g/kg/hr, or about 35 .mu.g/kg/hr, or about 40 .mu.g/kg/hr, or
about 45 .mu.g/kg/hr, or about 50 .mu.g/kg/hr.
[0090] In particular embodiments, the dexmedetomidine is
administered as a continuous intravenous dose for a period of time
of between about 1 and about 10 minutes, or between about 1 and
about 20 minutes, or between about 1 and about 30 minutes, or
between about 1 and about 2 hours, or between about 1 and about 3
hours, or between about 1 and about 4 hours, or between about 1 and
about 5 hours, or between about 1 and about 6 hours, or between
about 1 and about 7 hours, or between about 1 and about 8 hours, or
between about 1 and about 9 hours, or between about 1 and about 10
hours, or between about 1 and about 11 hours, or between about 1
and about 12 hours, or between about 1 and about 13 hours, or
between about 1 and about 14 hours, or between about 1 and about 15
hours, or between about 1 and about 16 hours, or between about 1
and about 17 hours, or between about 1 and about 18 hours, or
between about 1 and about 19 hours, or between about 1 and about 20
hours, or between about 1 and about 21 hours, or between about 1
and about 22 hours, or between about 1 and about 23 hours, or
between about 1 and about 24 hours. In preferred non-limiting
embodiments, the dexmedetomidine is administered as a continuous
dose for a period of time of between about 6 and about 24 hours. In
certain embodiments, the dexmedetomidine is administered as a
continuous dose for a period of time of about 6 hours, or about 7
hours, or about 8 hours, or about 9 hours, or about 10 hours, or
about 11 hours, or about 12 hours, or about 13 hours, or about 14
hours, or about 15 hours, or about 16 hours, or about 17 hours, or
about 18 hours, or about 19 hours, or about 20 hours, or about 21
hours, or about 22 hours, or about 23 hours, or about 24 hours.
[0091] In certain non-limiting embodiments, the administration of
dexmedetomidine comprises a first loading dose administered prior
to a second maintenance dose. When administered as a loading dose
followed by a maintenance dose, the loading dose can be a dose of
between about 0 .mu.g/kg and about 5 .mu.g/kg, or between about
0.005 .mu.g/kg and about 4.5 .mu.g/kg, or between about 0.005
.mu.g/kg and about 3 .mu.g/kg, or between about 0.005 .mu.g/kg and
about 2.5 .mu.g/kg, or between about 0.005 .mu.g/kg and about 2
.mu.g/kg, or between about 0.005 .mu.g/kg and about 1.5 .mu.g/kg,
or between about 0.005 .mu.g/kg and about 1 .mu.g/kg, or between
about 0.005 .mu.g/kg and about 0.5 .mu.g/kg, or between about 0.005
.mu.g/kg and about 0.25 .mu.g/kg, or between about 0 .mu.g/kg and
about 0.4 .mu.g/kg. In preferred non-limiting embodiments, the
loading dose is between about 0 .mu.g/kg and about 1.0 .mu.g/kg. In
particular embodiments, the loading dose is about 0.01 .mu.g/kg, or
about 0.025 .mu.g/kg, or about 0.05 .mu.g/kg, or about 0.1
.mu.g/kg, or about 0.2 .mu.g/kg, or about 0.25 .mu.g/kg, or about
0.3 .mu.g/kg, or about 0.35 .mu.g/kg, or about 0.4 .mu.g/kg, or
about 0.5 .mu.g/kg, or about 0.6 .mu.g/kg, or about 0.7 .mu.g/kg,
or about 0.8 .mu.g/kg, or about 0.9 .mu.g/kg, or about 1.0
.mu.g/kg, or about 1.1 .mu.g/kg, or about 1.2 .mu.g/kg, or about
1.3 .mu.g/kg, or about 1.4 .mu.g/kg, or about 1.5 .mu.g/kg, or
about 1.6 .mu.g/kg, or about 1.7 .mu.g/kg, or about 1.8 .mu.g/kg,
or about 1.9 .mu.g/kg, or about 2.0 .mu.g/kg, or about 2.1
.mu.g/kg, or about 2.2 .mu.g/kg, or about 2.3 .mu.g/kg, or about
2.4 .mu.g/kg, or about 2.5 .mu.g/kg. In certain embodiments, the
loading dose is about 3.0 .mu.g/kg, or about 3.5 .mu.g/kg, or about
4.0 .mu.g/kg, or about 4.5 .mu.g/kg, or about 4.0 .mu.g/kg, or
about 4.5 .mu.g/kg, or about 5.0 .mu.g/kg, or about 5.5 .mu.g/kg,
about 6.0 .mu.g/kg, or about 6.5 .mu.g/kg, or about 7.0 .mu.g/kg,
or about 7.5 .mu.g/kg, about 8.0 .mu.g/kg, or about 8.5 .mu.g/kg,
or about 9.0 .mu.g/kg, or about 9.5 .mu.g/kg, or about 10 .mu.g/kg,
or about 11 .mu.g/kg, or about 12 .mu.g/kg, or about 13 .mu.g/kg,
or about 14 .mu.g/kg, or about 15 .mu.g/kg, or about 16 .mu.g/kg,
or about 17 .mu.g/kg, or about 18 .mu.g/kg, or about 19 .mu.g/kg,
or about 20 .mu.g/kg, or about 21 .mu.g/kg, or about 22 .mu.g/kg,
or about 23 .mu.g/kg, or about 24 .mu.g/kg, or about 25 .mu.g/kg,
or about 27.5 .mu.g/kg, or about 30 .mu.g/kg, or about 32.5
.mu.g/kg, or about 35 .mu.g/kg, or about 40 .mu.g/kg, or about 45
.mu.g/kg, or about 50 .mu.g/kg.
[0092] In certain embodiments, the loading dose is below about 0.5
.mu.g/kg, or below about 0.45 .mu.g/kg, or below about 0.4
.mu.g/kg, or below about 0.35 .mu.g/kg, or below about 0.3
.mu.g/kg, or below about 0.25 .mu.g/kg, or below about 0.2
.mu.g/kg, or below about 0.15 .mu.g/kg, or below about 0.1
.mu.g/kg, or below about 0.05 .mu.g/kg, or below about 0.01
.mu.g/kg. In particular embodiments, no loading dose is
administered.
[0093] The loading dose can be administered for a period of time of
between about 1 and about 5 minutes, or between about 1 and about
10 minutes, or between about 1 and about 15 minutes, or between
about 1 and about 20 minutes, or between about 1 and about 25
minutes, or between about 1 and about 30 minutes, or between about
1 and about 45 minutes, or between about 1 and about 60 minutes.
Following the loading dose, the maintenance dose can be
administered for a period of time as described above for a single
continuous dose. In preferred non-limiting embodiments, the loading
dose is administered for a period of time of about 10 to about 20
minutes. In particular embodiments, the loading dose is
administered for a period of time of about 5 minutes, or about 7.5
minutes, or about 10 minutes, or about 12.5 minutes, or about 15
minutes, or about 20 minutes, or about 25 minutes, or about 30
minutes, or about 35 minutes, or about 40 minutes, about 45
minutes, or about 50 minutes, or about 55 minutes, or about 60
minutes.
[0094] In certain non-limiting embodiments, the dexmedetomidine,
when administered as a single continuous, loading or maintenance
dose, is administered for a period of time of about 1 hour to about
7 days, or about 1 hour to about 4 days, or about 1 hour to about
48 hours, or about 1 hour to about 36 hours, or about 1 hour to
about 24 hours, or about 1 hour to about 12 hours. In particular
non-limiting embodiments, the dexmedetomidine is administered as a
continuous infusion for less than about 72 hours, or less than
about 48 hours, or less than about 36 hours, or less than about 24
hours, or less than about 18 hours, or less than about 12 hours, or
less than about 6 hours, or less than about 3 hours, or less than
about 1 hour, or less than about 30 minutes.
[0095] In certain embodiments, the method reduces the amount of
rescue medication required. In one embodiment, the rescue
medication is a non-dexmedetomidine sedative. In particular
embodiments, the presently disclosed method reduces the amount of
sedative rescue medication required by between about 5% and about
100%, or between about 5% and about 75%, or between about 5% and
about 50%, or between about 5% and about 25%, or between about 5%
and about 15%.
[0096] In particular embodiments, the sedative rescue medication is
a benzodiazepine. Non-limiting examples of benzodiazepines include
clonazepam, diazepam, estazolam, flunitrazepam, lorazepam,
midazolam, nitrazepam, oxazepam, triazolam, temazepam,
chlordiazepoxide, and alprazolam. In particular embodiments, the
sedative is a barbiturate. Non-limiting examples of barbiturates
include amobarbital, pentobarbital, secobarbital, and
phenobarbital. Other examples of sedatives include chloral hydrate,
eszopiclone, zaleplon, zolpidem, and zopiclone.
[0097] In certain embodiments, the rescue medication is an
analgesic. In certain embodiments, the method reduces the amount of
analgesic rescue medication required. In particular embodiments,
the presently disclosed method reduces the amount of analgesic
rescue medication required by between about 5% and about 100%, or
between about 5% and about 75%, or between about 5% and about 50%,
or between about 5% and about 25%, or between about 5% and about
15%.
[0098] In one embodiment, the analgesic is an opioid. Non-limiting
examples of opioids include codeine, oxycodone, hydrocodone,
fentanyl, morphine, buprenorphine, hydromorphone, methadone,
tramadol, meperidine, oxymorphone, and pentazocine. In certain
embodiments, the analgesic is an N-methyl-D-aspartate antagonist
(NDMA). Non-limiting examples of NDMAs include ketamine, nitrous
oxide, and xenon. Other examples of analgesics include clonidine,
desflurane, isoflurane, and sevoflurane. The rescue medication may
be administered via perioral, parenteral, transnasal (for example,
a powder), rectal (for example, as a suppository), or topical
administration.
[0099] In one embodiment, the presently disclosed method reduces
incidence of neurological damage. In particular embodiments, the
presently disclosed method reduces the incidence of neurological
damage in one or more regions of the brain. Non-limiting examples
of brain regions in which the incidence of neurological damage is
reduced include cerebral cortex, basal ganglia, olfactory bulb,
hypothalamus, thalamus, epithalamus, midbrain, pons, cerebellum,
and medulla.
[0100] Non-limiting causes of neurological damage include, but are
not limited to, the administration of a sedative or analgesic
agent, seizure, asphyxia, epilepsy, concussion, cerebral
hemorrhage, cord shock, drowning, tumor, immunotherapy,
chemotherapy, iatrogenic free-radical toxicity, injury, ataxias,
surgery, cardiopulmonary bypass, cerebral palsy, cerebral ischemia,
cerebral anoxia injury, autoimmune neurodegeneration, myocardial
ischemia, myocardial infarct, stroke, atherosclerosis, acute
respiratory failure, coronary artery bypass graft, ulcerative
colitis, traumatic brain injury, spinal cord injury, spinal
muscular atrophy, vertebral disease, decompression sickness, fetal
alcohol syndrome, hepatitis-B, hepatitis-C, hepatitis-G, yellow
fever, dengue fever, encephalitis, liver disease, primary
cirrhosis, renal disease, pancreatitis, polycystic kidney disease,
H. pylori-associated gastric and duodenal ulcer disease, HIV
infection, toxoplasmosis, rubella, cytomegalovirus, tuberculosis,
meningitis, juvenile diabetes, lichenplanus, uveitis, Behcet's
disease, pure red cell aplasia, aplastic anemia, amyotrophic
lateral sclerosis, multiple sclerosis, nephrotic syndrome, and
combinations thereof.
[0101] In particular non-limiting embodiments, the resulting
neurological damage includes various types of neurocognitive,
psychocognitive, and/or neuromotor or motor impairment, or
combinations thereof. Such impairments can be delayed functions or
abilities, disrupted functions or abilities, loss of function or
ability, inability for develop or learn new abilities, and the
like. Non-limiting examples of neurocognitive and/or
psychocognitive impairments include learning, memory, executive
function, and visuospatial ability impairment. Non-limiting
examples of neuromotor impairments include strength, balance,
mobility impairment, and combinations thereof. In other
non-limiting embodiments, the neurological damage includes
developmental delay, cerebral palsy, mental retardation, visual
impairment, hearing impairment, autism, paralysis, hemiplegia, a
strain condition, a stress condition, a nervous dysfunction such as
convulsions, seizure, muscle stiffness, nervous strain and anxiety,
and combinations thereof. (See, e.g., Hintz et al. Pediatrics. 2005
June; 115(6):1645-51.).
[0102] The neurological damage impairments may be assessed by
well-established criteria including but not limited to an IQ test
(See, e.g., (Wechsler, J. Wechsler Preschool and Primary Scale of
Intelligence. San Antonio: The Psychological Corp., 1989), the
short-story module of the Randt Memory Test (See Randt C, Brown E.
Administration manual: Randt Memory Test. New York: Life Sciences,
1983), the Digit Span subtest and Digit Symbol subtest of the
Wechsler Adult Intelligence Scale-Revised (See Wechsler D. The
Wechsler Adult Intelligence Scale-Revised (WAIS-R). San Antonio,
Tex.: Psychological Corporation, 1981.), the Benton Revised Visual
Retention Test (See Benton A L, Hansher K. Multilingual aphasia
examination. Iowa City: University of Iowa Press, 1978), and the
Trail Making Test (Part B) (See Reitan R M. Validity of the Trail
Making Test as an indicator of organic brain damage. Percept Mot
Skills 1958; 8:271-6). Other non-limiting examples of
well-established criteria for determining neurological damage
include the Bayley Scales of Infant Development (BSID-II) Mental
Development Index assessment, the BSID-II Psychomotor Development
Index assessment, the Denver Developmental Screening Test, magnetic
resonance imaging, vision tests, and hearing tests. Other tests can
include standardized interaction and/or observation, such as
standardized assessments of socialization, hand-eye coordination,
motor control, ability to understand and use sounds and words, and
ability to recognize sounds and words.
[0103] Non-limiting examples of a reduction in the incidence of
neurological damage include a reduction in the severity of,
reduction in the number of, prevention of, or delay of the
development of one or more incidences of neurological damage, or a
combination thereof. In one non-limiting embodiment, a reduction in
the incidence of neurological damage includes a better score or
assessment as measured by one of the tests or assessments listed
above than if an effective amount of dexmedetomidine had not been
administered to the pediatric patient.
[0104] In particular embodiments, the neurological damage is
cellular degeneration or neuronal apoptosis. As used herein, the
term "cellular degeneration" refers to cell death as a result of a
stimulus, trauma, a pharmaceutical composition, or a pathologic
process. As used herein, the term "neuroapoptosis" or "neuronal
apoptosis" refers to neuronal cell death associated with programmed
cell death. In particular embodiments, the methods reduce the
incidence of neuroapoptosis.
[0105] Non-limiting examples of cells which can be protected by the
presently disclosed methods include neurons and glial cells.
Non-limiting examples of neurons which can be protected by the
presently disclosed methods include Renshaw cells, Purkinje cells,
hippocampal basket cells, cerebellum basket cells, cortex basket
cells, cortex interneurons, cerebellum interneurons, pyramidal
cells, granule cells, anterior horn cells, and motor neurons.
Non-limiting examples of glial cells which can be protected by the
presently disclosed methods include neurolemmocytes, satellite
cells, microglia, oligodendroglia, and astroglia.
[0106] In certain embodiments, the neurological damage includes
cell shrinkage, chromatin-clumping with margination, formation of
membrane-enclosed apoptotic bodies, and Ash neuronal necrosis.
[0107] In one embodiment, the administration of dexmedetomidine
reduces the incidence of neurological damage in a cortex lamina
layer. In certain embodiments, the reduction occurs in one or more
of the cortex lamina layers I-IV. In one embodiment, the reduction
in neurological damage occurs in a cortex lamina layer I. In
particular embodiments, the reduction in neurological damage occurs
in cortex lamina layer II. In certain embodiments, the reduction
occurs in both cortex lamina layer I and II.
7. EXAMPLES
[0108] The following examples are merely illustrative of the
presently disclosed subject matter and they should not be
considered as limiting the scope of the invention in any way.
Example 1: Dexmedetomidine Study in Neonates
[0109] Initial 30 Patient Study
[0110] A 30-subject, open-label, multicenter, safety, efficacy and
pharmacokinetic study of dexmedetomidine was conducted on neonates
aged.gtoreq.28 weeks to .ltoreq.44 weeks gestational age who
required sedation in an intensive care setting for a minimum of 6
hours. The present study investigated the efficacy,
pharmacokinetics, and safety of dexmedetomidine safety at three
different dose levels in neonates, ages.gtoreq.28 weeks to
.ltoreq.44 weeks gestational age, administered as a loading dose
followed by continuous infusion for a minimum of 6 hours and up to
24 hours in the neonatal intensive care unit (NICU), cardiac
intensive care unit (CICU), or PICU. Gestation age (in weeks) was
calculated as the time elapsed between the first day of the last
menstrual period and the day of enrollment. If pregnancy was
achieved using assisted reproductive technology, gestational age
was calculated by adding two weeks to the gestational age as
calculated above.
[0111] The patients selected for the study were initially intubated
and mechanically ventilated preterm neonates.gtoreq.28 weeks to
<36 weeks gestational age and term neonates born at .gtoreq.36
weeks to .ltoreq.44 weeks gestational age. The former were assigned
to Group 1 and the latter were assigned to Group II. The subjects
weighed over 1,000 g at the time of enrollment.
[0112] The cardiovascular system in newborns has characteristics
that could negatively impact the use of dexmedetomidine in this
population. Unlike older infants, children, and adults, the newborn
myocardium is not able to increase contractility to increase
cardiac output in response to metabolic demands. Instead, neonates
are highly dependent on their HR to increase cardiac output. As a
result, bradycardia, a known effect of dexmedetomidine, could
decrease cardiac output in neonates. For this reason, the doses
selected for study in this population were intentionally lower than
those typically used for sedation of older pediatric patients. The
lower doses were expected to mitigate an adverse effect of
bradycardia, while the immaturity of the blood brain barrier in
this population could facilitate the sedating properties of
dexmedetomidine because of its high lipid solubility and
potentially higher cerebrospinal fluid concentrations; therefore,
the lowest dose, 0.05 .mu.g/kg loading dose over 10 or 20 minutes
followed by 0.05 .mu.g/kg hr maintenance dose, was expected to
effect some sedation in mechanically ventilated subjects in this
age group. The highest dose, 0.2 .mu.g/kg loading dose followed by
0.2 .mu.g/kg/hr, was not expected to cause bradycardia.
[0113] Each subject received a loading dose of dexmedetomidine over
10 or 20 minutes followed by the appropriate continuous infusion
maintenance dose of dexmedetomidine for a minimum of 6 but not more
than 24 hours. The dose levels administered to each subject are
given in Table 1 below. Subjects were sequentially assigned to the
dose levels.
TABLE-US-00001 TABLE 1 Dose Levels for Each Age Group Treatment
Group Age Group Age Group I .gtoreq. 28 II .gtoreq. 36 weeks weeks
to < 36 to .ltoreq. 44 Continuous weeks weeks Loading Infusion
Dose gestational gestational Dose Rate Level age (n) age (n)
.mu.g/kg .mu.g/kg/hr 1 6 8 0.05 0.05 2 0 8 0.1 0.1 3 0 8 0.2
0.2
[0114] The dexmedetomidine administered was a Precedex.RTM.
dexmedetomidine HCl injection manufactured by Hospira, Inc.
Dexmedetomidine hydrochloride (HCl) injection (100 .mu.g/mL, base)
was supplied by Hospira to the investigative sites for infusion.
Study medication was prepared (diluted) by the site pharmacy. The
loading doses of dexmedetomidine were diluted in 0.9% sodium
chloride or dextrose 5% in water to one of the following
concentrations: 4 .mu.g/mL solution, 2 .mu.g/mL solution, 1
.mu.g/mL solution, or 0.5 .mu.g/mL solution. Dexmedetomidine was
infused using a controlled infusion device. In order to ensure
proper infusion, dexmedetomidine was not administered directly into
the pulmonary artery.
[0115] Dexmedetomidine was administered as a two-stage infusion. A
10- or 20-minute loading dose infusion of dexmedetomidine was
administered followed by a continuous fixed maintenance dose
infusion of dexmedetomidine for a minimum of 6 and up to 24 hours
post-operatively. The dexmedetomidine for maintenance infusion was
diluted at the same concentration as for the loading dose of
dexmedetomidine. The dexmedetomidine for both the loading and the
maintenance infusion was administered at the site of insertion of
the IV catheter to avoid flushing the drug. Dexmedetomidine was
administered through a designated IV line for dexmedetomidine.
[0116] Sedation dosages were calculated using the subject's most
recently measured weight prior to commencement of dexmedetomidine.
No dosage adjustments were needed for day to day weight
fluctuations because the dexmedetomidine duration spanned a maximum
of 24 hours.
[0117] Exposure to dexmedetomidine is summarized by gestational age
in Table 2 (loading dose), Table 3 (maintenance dose), and Table 4
(total dose/time; time of exposure<6 hours, <12 hours, <24
hours, >0-<6 hours, .gtoreq.6-<12 hours, .gtoreq.12-<24
hours, and 24 hours). Median exposure to dexmedetomidine is
summarized in Tables 2-4 below. The median data were chosen due to
variability in data. Median dexmedetomidine exposure was highest in
age Group II, dose level 3. For age Group I, 2 subjects each
received infusions lasting between >0-<6 hours,
.gtoreq.6-<12 hours, and .gtoreq.12-<24 hours. For age Group
II, the majority of subjects (n=17, 70.8%) received infusions
between .gtoreq.6-<12 hours, with a median duration of just over
6 hours (370 minutes). Subjects in dose level 3 received the
longest maintenance infusion in age Group II at a median of 961.5
minutes (16 hours) compared to the other 2 cohorts in this age
group at a median of 360.0-365.0 minutes (approximately 6 hours).
All subjects completed the treatment, receiving a minimum of 6
hours of maintenance infusion.
TABLE-US-00002 TABLE 2 Median Loading Dose of Dexmedetomidine
Exposure Age Group I.sup.a Age Group II.sup.a Dose Dose Dose Dose
Level 1 Level 1 Level 2 Level 3 dexmedeto- dexmedeto- dexmedeto-
dexmedeto- midine midine midine midine Total Age 0.05.sup.b
0.05.sup.b 0.1.sup.b 0.2.sup.b Group II.sup.a Median Parameter (N =
6) (N = 8) (N = 8) (N = 8) (N = 24) Loading dose N 6 8 8 8 24 Total
loading dose (.mu.g) 0.07 0.18 0.31 0.70 0.31 Duration (min) 10.0
10.0 10.0 10.0 10.0 .sup.aAge Group I .gtoreq. 28 to < 36 weeks
gestational age; Age Group II .gtoreq. 36 to .ltoreq. 44 weeks.
.sup.bUnits are .mu.g/kg for loading dose and .mu.g/kg/hr for
maintenance dosing (continuous infusion).
TABLE-US-00003 TABLE 3 Median Maintenance Dose of Dexmedetomidine
Exposure Age Group I.sup.a Age Group II.sup.a Dose Level Dose Level
1 1 Dose Level Dose Level dexmedeto- dexmedeto- 2 3 midine midine
dexmedeto- dexmedeto- Total Age 0.05.sup.b (N = 0.05.sup.b (N =
midine 0.1.sup.b midine 0.2.sup.b Group II.sup.a Median Parameter
6) 8) (N = 8) (N = 8) (N = 24) Maintenance dose N 6 8 8 8 24 Total
maintenance dose 1.30 1.08 1.87 12.20 1.87 (.mu.g) Duration (min)
1407.5 360.0 365.0 961.5 360.0 .sup.aAge Group I .gtoreq. 28 to
< 36 weeks gestational age; Age Group II .gtoreq. 36 to .ltoreq.
44 weeks. .sup.bUnits are .mu.g/kg for loading dose and .mu.g/kg/hr
for maintenance dosing (continuous infusion).
TABLE-US-00004 TABLE 4 Median Total Dose of Dexmedetomidine
Exposure Age Group I.sup.a Age Group II.sup.a Dose Level Dose Level
1 1 Dose Level Dose Level dexmedeto- dexmedeto- 2 3 midine midine
dexmedeto- dexmedeto- Total Age 0.05.sup.b (N = 0.05.sup.b (N =
midine 0.1.sup.b midine 0.2.sup.b Group II.sup.a Median Parameter
6) 8) (N = 8) (N = 8) (N = 24) Duration of exposure > 0-< 6
hours N 0 0 0 0 0 Total dose (.mu.g) -- -- -- -- -- Duration (min)
-- -- -- -- -- Duration of exposure .gtoreq. 6-< 12 hours N 2 8
7 2 17 Total dose (.mu.g) 0.51 1.26 2.14 4.06 1.52 Duration (min)
370.0 370.0 370.0 370.0 370.0 Duration of exposure .gtoreq. 12-<
24 hours N 2 0 1 5 6 Total dose (.mu.g) 1.97 -- 7.76 13.32 12.96
Duration (min) 1417.5 -- 1370.0 1040.0 1070.0 Duration of exposure
.gtoreq. 24 hours N 2 0 0 1 1 Total dose (.mu.g) 1.35 -- -- 15.75
15.75 Duration (min) 1450.0 -- -- 1460.0 1460.0 .sup.aAge Group I
.gtoreq. 28 to < 36 weeks gestational age; Age Group II .gtoreq.
36 to .ltoreq. 44 weeks. .sup.bUnits are .mu.g/kg for loading dose
and .mu.g/kg/hr for maintenance dosing (continuous infusion).
[0118] Subjects in age Group I received a median total loading dose
of 0.07 .mu.g with a median duration of 10 minutes and a median
total maintenance dose of 1.30 .mu.g over 1407.5 minutes (23.5
hours). Subjects in age Group II received a median total loading
dose of 0.18-0.70 .mu.g over 10 minutes and a median total
maintenance dose of 1.08-12.20 .mu.g over 360-961.5 minutes (6-16
hours).
[0119] Efficacy evaluations were conducted by assessing the
frequency of sedation using the Neonatal Pain, Agitation, and
Sedation Scale (N-PASS), developed to assess sedation and
pain/agitation in neonates. The N-PASS includes 5 criteria to
assess sedation levels, pain, and agitation in neonates. The
indicators are as follows: 1) crying/irritability, 2)
behavior/state, 3) facial expression, 4) extremities/tone, and 5)
vital signs (i.e., HR, RR, SBP, DBP, and SpO.sub.2). Whenever
possible, the same Investigator or designee obtained N-PASS scores,
according to the schedule of activities as shown in Table 5.
[0120] The evaluation for the presence of paradoxical reactions
(notably rage) was monitored in conjunction with all N-PASS
assessments. Rage was protocol-defined and occurred when either the
Crying/Irritability or Behavior/State assessment criteria in the
N-PASS merited a score of 2. For each of the 5 assessment criteria,
the subject would be given one number, -2, -1, 0, +1, or +2. The
subject might have some criteria score in the negative sedation
side, and other criteria in the positive pain/agitation side, but
for a single criterion would score either on the sedation or the
pain side, not both. If subject gestational age was <30 weeks, 1
was added into the pain score.
TABLE-US-00005 TABLE 5 N-PASS-Neonatal Pain, Agitation and Sedation
Scale Sedation/ Assessment Sedation Pain Pain/Agitation Criteria -2
-1 0/0 1 2 Crying No cry with Moans or No sedation/ Irritable or
High-pitched or Irritability painful stimuli cries No pain crying
at silent-continuous minimally signs intervals cry Inconsolable
with painful Consolable stimuli Behavior No arousal to Arouses No
sedation/ Restless, Arching, kicking State any stimuli minimally to
No pain squirming Constantly awake No stimuli signs Awakens or
spontaneous Little frequently Arouses movement spontaneous
minimally/no movement movement (not sedated) Facial Mouth is lax
Minimal No sedation/ Any pain Any pain Expression No expression
expression No pain expression expression with stimuli signs
intermittent continual No sedation/ Intermittent Continual
Extremities No grasp reflex Weak grasp No pain clenched clenched
toes, Tone Flaccid tone reflex signs toes, fists or fists, or
finger .dwnarw. muscle tone finger splay splay Body is not Body is
tense tense Vital Signs No variability <10% No sedation/ .uparw.
10-20% .uparw. > 20% from HR, RR, with stimuli variability No
pain from baseline BP, Hypoventilation from signs baseline
SaO.sub.2 .ltoreq. 75% with SaO.sub.2 or apnea baseline SaO.sub.2
76- stimulation-slow with stimuli 85% with .uparw. stimulation- Out
of quick .uparw. sync/fighting vent
[0121] Morphine or fentanyl and/or midazolam could be given for
rescue as indicated by a total N-PASS score>3 or by clinical
judgment. The dexmedetomidine infusion could be continued during
and after the subject was extubated; however, the minimum duration
of dexmedetomidine infusion was 6 hours and the maximum duration of
infusion was 24 hours. Efficacy measures included the use of rescue
medication for sedation or analgesia (incidence and amount used)
during dexmedetomidine infusion.
[0122] Rescue medication was administered as needed for sedation
(midazolam) and pain (fentanyl or morphine), during dexmedetomidine
administration based on results of the N-PASS sedation/pain scale.
Rescue therapy was indicated when the N PASS total score>3 and
the selection of sedative rescue or analgesic rescue was at the
discretion of the Investigator. For any bolus administration of
rescue therapy, the following sequence of events occurred: The
N-PASS score was obtained prior to the administration of rescue
medication and within 5 minutes after administration of midazolam.
The rescue medicine for sedation was midazolam and the rescue
medication for pain was either fentanyl or morphine. Midazolam was
administered based on labeling for pediatrics at a recommended dose
of 0.05 to 0.15 mg/kg per dose. Rescue fentanyl for pain was
administered in a 0.5 to 2 .mu.g/kg bolus or 1 to 2 .mu.g/kg/hr
continuous infusion. For continuous infusions of fentanyl, the
N-PASS was recorded immediately prior to initiating the continuous
infusion. Rescue morphine was administered as a 0.025 to 0.1 mg/kg
bolus or 0.01 to 0.02 mg/kg/hr continuous infusion. For continuous
infusions of morphine, the N-PASS was recorded immediately prior to
initiating the continuous infusion.
[0123] Summary statistics for the dexmedetomidine loading doses and
maintenance infusion doses are shown in Table 8A below.
TABLE-US-00006 TABLE 5A Summary Statistics of Dosing-Related Data
0.05 .mu.g/kg + 0.10 .mu.g/kg + 0.20 .mu.g/kg + Dose-Related
Variable 0.05 .mu.g/kg/h 0.10 .mu.g/kg/h 0.20 .mu.g/kg/h Loading
dose (ng) Mean 125.400 298.650 664.250 (SD) (58.239) (51.136)
(114.030) Median 120.000 312.000 676.000 Min, Max 56.00, 217.50
200.10, 363.00 460.00, 830.00 n 10 8 8 Maintenance infusion Mean
1147.563 2513.618 10579.833 dose (ng) (SD) (546.668) (2004.047)
(5174.104) Median 1080.000 1872.000 12195.750 Min, Max 357.00,
2197.67 1317.33, 7425.00 2760.00, 16756.00 n 10 8 8 Total dose (ng)
Mean 1272.963 2812.268 11244.083 (SD) (548.969) (2023.889)
(5249.609) Median 1260.000 2184.000 12960.750 Min, Max 416.50,
2292.67 1517.43,7755.00 3220.00, 17464.00 n 10 8 8 Loading infusion
Mean 0.167 0.229 0.208 duration (h) (SD) (0.000) (0.086) (0.077)
Median 0.167 0.167 0.167 Min, Max 0.17, 0.17 0.17, 0.33 0.17, 0.33
n 10 8 8 Maintenance infusion Mean 11.292 8.223 15.454 duration (h)
(SD) (8.523) (5.774) (6.887) Median 6.000 6.083 16.025 Min, Max
6.00, 24.00 6.00, 22.50 6.00, 24.00 n 10 8 8 Time between start of
Mean 18.500 14.500 13.125 doses (min) (SD) (20.823) (4.629) (4.291)
Median 10.000 12.000 11.000 Min, Max 10.00, 75.00 10.00, 20.00
10.00, 20.00 n 10 8 8 Time from end of 1.sup.st Mean 8.500 0.750
0.625 to beginning of 2.sup.nd (SD) (20.823) (1.035) (0.744)
infusion (min) Median 0.000 0.500 0.500 Min, Max 0.00, 65.00 0.00,
3.00 0.00, 2.00 n 10 8 8
[0124] Safety measures included collection of adverse events
(adverse events), heart rate (HR in beats per minute [bpm]),
systolic blood pressure (SBP in millimeters of mercury [mmHg]),
diastolic blood pressure (DBP in millimeters of mercury [mmHg]),
mean arterial pressure (MAP in millimeters of mercury [mmHg]),
oxygen saturation by pulse oximetry (SpO.sub.2 in percentage), and
respiratory rate (RR in breaths/minute [breaths/min]) or ventilator
settings, laboratory results, and electrocardiogram (ECG)
monitoring.
[0125] Arterial, venous, or capillary blood samples (0.15 mL each)
for pharmacokinetic analysis were obtained at six or seven
protocol-designated times for subjects in age Group I depending
upon weight (.gtoreq.28 weeks to .ltoreq.36 weeks gestational age)
and at seven designated times for subjects in age Group II
(.gtoreq.36 weeks through .ltoreq.44 weeks gestational age).
[0126] Chemistry, hematology and urinalysis samples were obtained
for the laboratory tests according to the following schedule of
study activities: at screening, after five hours of maintenance but
before discontinuation of dexmedetomidine and within 24 hours
following the discontinuation of dexmedetomidine infusion. In
addition, subjects who were s/p CPB had a sample drawn for ALT
level following CPB, but no later than 1 hour from the commencement
of dexmedetomidine (this constituted the ALT at baseline). All
blood and urine samples were collected in appropriately labeled
tubes and sent to the local laboratory for analysis.
[0127] Liver function tests (LFTs) were obtained pre- and post
treatment and compared for evidence of hepatic dysfunction. Liver
function tests were obtained during the following periods: at
screening, after five hours of maintenance but before
discontinuation, and in close proximity to 24 hours after
discontinuation of the infusion or on the day of discharge,
whichever came first. In addition, subjects who were s/p CPB had a
sample drawn for ALT level following CPB, but no later than 1 hour
from the beginning of the dexmedetomidine infusion. This
constituted the ALT at baseline and was not used in reference to
exclusion criteria. Liver function tests were defined as: aspartate
aminotransferase (AST), ALT, alkaline phosphatase, and total
bilirubin. Hepatotoxicity was defined by an ALT>156 U/L or
a.gtoreq.30% increase from screening value, whichever was
greater.
[0128] The statistical analyses were performed using SAS'
Statistical Software System (SAS Institute, Inc., Cary, N.C.),
version 9.1. All statistical tests were 2 sided and p
values.ltoreq.0.0500, after rounding to 4 decimal places, were
considered statistically significant unless otherwise specified. In
general, missing data were not imputed. For continuous variables,
N, mean, median, SD, minimum, Q1, Q3 and maximum are presented. The
mean and median was displayed to 1 decimal place more than the raw
value. The standard deviation (SD) is displayed to 2 decimal places
more than the raw value. For categorical variables, N and percent
is shown. All percentages were reported to 1 decimal place.
[0129] For the final analyses, treatment differences by age groups
were assessed for continuous variables using two-way analysis of
variance (ANOVA) when assumption of normal distribution is
reasonable or by nonparametric tests when this assumption was not
met. For ordered categorical variables, the Cochran-Mantel-Haenszel
(CMH) test was used. If treatment differences are significant, a
pairwise comparison between dose levels was performed. All efficacy
variables were analyzed while on dexmedetomidine.
[0130] Dexmedetomidine was effective at sedating critically ill,
initially intubated and mechanically ventilated premature infants,
.gtoreq.28 to <36 weeks. No subject in age Group I received
rescue midazolam for sedation during dexmedetomidine infusion. At
the doses used in this trial, up to 0.2 .mu.g/kg/hr,
dexmedetomidine was moderately effective at sedating term neonates.
In age Group II, a total of 4 subjects (16.7%) received rescue
midazolam (mean dose 0.22 mg/kg) for sedation during
dexmedetomidine infusion.
[0131] Most premature neonates in age group I did not require
additional medication for pain while on dexmedetomidine infusion.
One subject (16.7%) in age group I received rescue medication for
analgesia during the study infusion. In contrast, more of the term
neonates in age group II (58.3%) received rescue medication for
analgesia during the study infusion. The increased analgesic
requirements in age group II, in particular dose level 3, most
likely reflects the higher proportion of post-operative surgical
subjects.
[0132] All dose levels spent a low period of time with a total
N-PASS score>3 indicating most subjects were adequately sedated
and not manifesting signs of pain/agitation. Generally, trends in
mean change from baseline in vital signs were not clinically
meaningful.
[0133] Premature neonates, 28 to <36 weeks gestational age,
appeared to have lower clearance than term neonates which resulted
in higher dose-adjusted exposure. These parameters were well
estimated at 1 dose level (0.05 .mu.g/kg) for age Group I (28 to
<36 weeks gestational age) and for all 3 dose levels (0.05
.mu.g/kg, 0.1 .mu.g/kg, and 0.2 .mu.g/kg) for age Group II
(.gtoreq.36 to weeks gestational age). The younger subjects
appeared to have lower clearance (0.41 L/hr/kg at 0.05 .mu.g/kg
dose level in age Group I) than older subjects (0.61 L/hr/kg at
0.05 .mu.g/kg dose level in age Group II) which resulted in higher
dose-adjusted exposure. This finding is difficult to interpret
because of the lack of pharmacokinetic data available at the 0.1
.mu.g/kg and 0.2 .mu.g/kg dose levels in the younger subjects.
[0134] The results of the pharmacokinetic analysis suggest volume
of distribution at steady state, weight adjusted (V.sub.ssw) and
the apparent terminal elimination half-life (t.sub.1/2) were
similar across dose levels and age groups. In addition,
dexmedetomidine exposure appeared to be dose proportional within
the older subjects (age Group II). Dose proportionality within the
younger subjects (age Group I) could not be assessed. This finding
is difficult to interpret because of the lack of pharmacokinetic
data available at the 0.1 .mu.g/kg and 0.2 .mu.g/kg dose levels in
the younger subjects. The lower clearance in this age group and
higher concentrations are consistent with the greater efficacy
observed in the premature neonates (no subjects required rescue
midazolam for sedation and 1 subject required rescue medication for
analgesia) compared to the term neonates (4 subjects required
rescue midazolam for sedation and 14 subjects required rescue
medication for analgesia). The V.sub.ssw and the t.sub.1/2 were
similar across dose levels and age groups.
[0135] Dexmedetomidine was safe and well tolerated in both age
groups and at all doses. The adverse effect profile observed is
typical of the critically ill, high risk pediatric population and
post-operative surgical patients. Treatment-emergent adverse
effects were experienced by 2 subjects (33.3%) in age Group I and
by 15 subjects (62.5%) in age Group II. In age Group I, dose level
1, no treatment-emergent adverse effects were reported by more than
1 subject. In age Group II, events reported by more than 1 subject
were hypokalemia, decreased blood potassium, anger, atelectasis,
and pleural effusion. These events were more common and expected in
the post-operative open heart surgery subjects.
[0136] The time to successful extubation was explored in
Precedex-exposed subjects using Kaplan-Meier estimates. Results for
this section are not clinically meaningful and therefore are not
further discussed due to the high variability in medical history
factors.
[0137] Most treatment-emergent adverse effects were assessed as not
related to treatment, only 2 subjects in the study (in age Group
II) experienced treatment-emergent adverse effects assessed as
related to treatment. There were no severe treatment-emergent
adverse effects reported, 2 subjects in each age group experienced
moderate treatment-emergent adverse effects, all other subjects
experienced mild treatment-emergent adverse effects. There were no
treatment-emergent serious adverse effects leading to death, no
other treatment-emergent serious adverse effects, and no
treatment-emergent adverse effects that led to dexmedetomidine
discontinuation. There were no dose-limiting toxicities that led to
dexmedetomidine discontinuation (persistent bradycardia, persistent
hypotension, or respiratory depression).
[0138] In general, mean changes from baseline were not clinically
significant for laboratory parameters, vital signs, physical
examination, or ECGs. Dexmedetomidine was effective at sedating
critically ill, initially intubated and mechanically ventilated
premature infants. No subject in age Group I received rescue
midazolam for sedation during the study infusion. At the doses used
in this trial, up to 0.2 .mu.g/kg/hr, dexmedetomidine was
moderately effective at sedating term neonates. Most premature
neonates in age Group I did not require additional medication for
pain while on dexmedetomidine infusion. In contrast, more of the
term neonates in age Group II (58.3%) received rescue medication
for analgesia during the study infusion. The increased analgesic
requirements in age Group II, in particular dose level 3, most
likely reflects the higher proportion of post-operative surgical
subjects. Premature neonates appeared to have lower plasma
clearance than term neonates which resulted in higher dose-adjusted
exposure and greater efficacy. No subjects discontinued the trial
due to treatment-emergent adverse effects. Dexmedetomidine was safe
and well tolerated in both age groups and at all doses. The adverse
effect profile observed is typical of the critically ill, high risk
pediatric population studied.
[0139] Additional 6 Patient Cohort
[0140] After the study had been initiated with the first original
30 patients, an additional six patients were enrolled in and
completed the study (hereinafter the "additional cohort"). The
study protocol for the study conducted on the additional cohort is
as described above. The additional six patients were neonates
aged.gtoreq.28 weeks to <36 weeks gestational age that required
sedation in an intensive care setting for a minimum of 6 hours.
These six patients were in dose level 2 and received a loading dose
of 0.1 .mu.g/kg and a maintenance dose of 0.1 .mu.g/kg. The dose
levels for each age group for the 36 total patients that received
dexmedetomidine in this study are given in Table 6 below.
TABLE-US-00007 TABLE 6 Dose Levels for Each Age Group Treatment
Group Age Group Age Group I .gtoreq. 28 weeks II .gtoreq. 36 weeks
Continuous to < 36 weeks to .ltoreq. 44 weeks Infusion
gestational gestational Loading Rate Dose Level age (n) age (n)
Dose .mu.g/kg .mu.g/kg/hr 1 6 8 0.05 0.05 2 6 8 0.1 0.1 3 0 8 0.2
0.2
[0141] The mean gestational age for the 6 subjects in the
additional cohort was 32.5 weeks. There were 3 males and 3 females.
The mean weight was 1.71 kg and the mean height was 42.75 cm. The
reason for intubation was respiratory disease in 5 of the subjects
and sepsis in 1 subject.
[0142] All 6 subjects in the additional cohort had received prior
therapies before entering this study; the most common of these were
anti-infectives, nutrition products, and midazolam or fentanyl. All
6 subjects received concomitant therapies; the most common of these
were anti-infectives and nutrition products. All 6 subjects
received a wide variety of therapies post-dexmedetomidine
infusion.
[0143] None of the 6 subjects in the additional cohort required
rescue midazolam or morphine during the dexmedetomidine infusion.
Only one subject (16.7%) required rescue medication for analgesia
during the dexmedetomidine infusion and was administered 2 .mu.g
(0.98 .mu.g/kg) fentanyl. The duration of the dexmedetomidine
infusion in this subject was 6.5 hours. This subject had a medical
history of gastroschisis requiring surgery for placement of a silo
as well as respiratory distress syndrome requiring intubation, both
ongoing at the time of screening. The subject requiring rescue
analgesia was the only subject to have a total N-PASS score below
3, which the subject had for 0.25 hours due to an infiltrated
I.V.
[0144] The geometric means of plasma pharmacokinetic parameters of
dexmedetomidine following a loading dose and a maintenance dose in
the cohort for the study addendum (age group I, dose level 2) are
shown in Table 7 below.
TABLE-US-00008 TABLE 7 Geometric Mean Plasma Pharmacokinetic
Parameters for Additional Cohort Patients Age Group I.sup.a Dose
Level 2 DEX Loading Dose = 0.1 .mu.g/kg Pharmacokinetic Parameter
Maintenance Dosing = 0.1 (units) .mu.g/kg/hr (N = 6) CL (L/hr) 0.48
(n = 2) CL.sub.w (L/hr/kg) 0.29 (n = 2) AUC (0-Last) [(pg/mL)hr]
708.09 AUC (0-Infinity) [(pg/mL)hr] 4305.31 (n = 2) AUC
(0-Infinity).sub.Dose 2102.55 (n = 2) [(pg/mL)hr/.mu.g] C.sub.max
(pg/mL) 107.22 V.sub.d (L) 5.71 (n = 2) V.sub.dw (L/kg) 3.47 (n =
2) V.sub.ss (L) 6.25 (n = 2) V.sub.ssw (L/kg) 3.79 (n = 2)
t.sub.1/2 (hr) 8.32 (n = 2) .sup.aAge group I = .gtoreq. 28 to <
36 weeks gestational age
[0145] The weight adjusted clearance (CL.sub.w) of DEX in the 2
subjects evaluated in the additional cohort was similar to the 1
subject evaluated in age group I, dose level 1 and again lower than
observed in age group II subjects. Consistent with the difference
in clearance, the dose-adjusted area under the concentration-time
curve from zero to infinity, AUC (0-Infinity), evaluated in the
additional cohort (n=2), was 4.6 times higher (2102.55 versus
461.04 (pg/mL)hr than that calculated for age group II across all
dose levels (n=12). In a similar manner, the concentration at
steady-state (C.sub.ss) was higher in the additional cohort than in
the same dose level in age group II (369.67 versus 170.53 pg/mL).
However, the maximum concentration (C.sub.max) was actually lower
in the additional cohort versus the same dose level in age group
II, 107.22 versus 122.43 pg/mL, respectively. The weight adjusted
volume of distribution at steady-state (V.sub.ssw) was slightly
larger in the additional cohort compared to the same dose level in
age group II (3.79 versus 2.85 L/kg) and the apparent terminal
elimination half-life (t.sub.1/2) was longer at 8.32 versus 4.77
hours, respectively.
[0146] Dexmedetomidine was safe and well tolerated in both age
groups and at all doses, including the additional cohort. The
adverse events profile observed in the additional cohort is typical
of the critically ill, high risk pediatric population.
[0147] The limited information from the premature neonates makes
interpretation of the effect of age on the pharmacokinetics of
dexmedetomidine difficult. However, based on the two dose levels
(0.05 and 0.1 .mu.g/kg) tested in age group 1 in the original 30
patient group and the additional cohort, it appeared that clearance
was lower, which resulted in total exposure (AUC) that was 4.4 to
4.6 times larger in the premature neonates (n=3) than the term
neonates (n=12). This finding is also consistent with higher
C.sub.ss levels in the premature neonates in age group I, dose
levels 1 and 2 compared to the term neonates. The lower clearance
in the premature neonates and higher concentrations are consistent
with the greater efficacy observed in the premature neonates in
both dose levels (no subjects required rescue midazolam for
sedation and 2 subjects required rescue medication for analgesia)
compared with the term neonates (4 subjects required rescue
midazolam for sedation and 14 subjects required rescue medication
for analgesia).
[0148] The C.sub.max and AUC (0-last) appeared lower in the
additional cohort compared to the same dose level from the age
group II population. These values were: C.sub.max 107.22 versus
122.43 pg/mL and AUC(0-Last) 708.09 versus 813.26 (pg/mL)hr,
respectively. Lower clearance, higher concentrations, and greater
efficacy were observed in the additional cohort of premature
neonates and consistent with what was observed in the other
premature neonate cohort compared to the term neonates in the
original 30 patient population.
[0149] Most premature neonates in age group I in the additional
cohort and in the original 30 patient population data did not
require additional medication for pain while on dexmedetomidine
infusion. One subject (16.7%) in each dose level of age group 1
received rescue medication for analgesia during the study infusion.
In contrast, in the original 30 patient population, more of the
term neonates in age group II (58.3%) received rescue medication
for analgesia during the study infusion. The increased analgesic
requirements in age group II, in particular dose level 3, most
likely reflects the higher proportion of postoperative surgical
subjects. Subjects in the additional cohort and in the original 30
patient population data spent a low period of time with a total
N-PASS score>3, indicating that most subjects were adequately
sedated and not manifesting signs of pain/agitation. Generally,
trends in changes from baseline in vital signs in the additional
cohort and in the interim analyses data were not clinically
meaningful.
[0150] Median exposure to dexmedetomidine is summarized in Table 8
below. The median data were chosen due to variability in data.
Subjects in age group I, dose level 2 had a lower median total
maintenance dose and duration of dexmedetomidine exposure compared
to age group I, dose level 1 from the interim analyses:
specifically, 1.14 .mu.g versus 1.30 .mu.g with a median duration
of 375.0 minutes (6.25 hours) versus 1407.5 minutes (23.5 hours),
respectively. Subjects in age group I, dose level 2 had a lower
median total maintenance dose but similar duration of
dexmedetomidine exposure compared with age group II from the
interim analyses at the same dose level: specifically, 1.14 .mu.g
versus 1.87 .mu.g with a median duration of 375.0 minutes (6.25
hours) versus 365.0 minutes (6.1 hours), respectively. Five of the
6 subjects received infusions lasting.gtoreq.6-<12 hours with a
median dose of 1.26 .mu.g and duration of 380 minutes (6.3 hours)
and 1 subject.gtoreq.12-<24 hours received a total dose of 4.06
.mu.g and duration of 1285.0 minutes (21.4 hours). All subjects
completed the treatment, receiving a minimum of 6 hours of
maintenance infusion.
TABLE-US-00009 TABLE 8 Median Dose and Duration of Dexmedetomidine
Exposure Age Group 1.sup.a Median Parameter Dose Level 2 DEX
0.1.sup.b (N = 6) Loading dose N 6 Total loading dose (.mu.g) 0.18
Duration (min) 20 Maintenance dose N 6 Total maintenance dose
(.mu.g) 1.14 Duration (min) 375.0 Duration of exposure .gtoreq.
6-< 12 hours N 5 Total dose (.mu.g) 1.26 Duration (min) 380.0
Duration of exposure .gtoreq. 12-< 24 hours N 1 Total dose
(.mu.g) 4.06 Duration (min) 1285.0 .sup.aAge group I .gtoreq. 28 to
< 36 weeks gestational ages .sup.bUnits are .mu.g/kg for loading
dose and .mu.g/kg/hr for maintenance dosing (continuous
infusion).
[0151] There was variability between subjects for most hematology
tests. In general, no evidence of systematic change for any
hematologic variable, chemistry variable, or urinalysis variable
were found. Treatment-emergent adverse events pertaining to
laboratory results were hypoalbuminemia (n=3) and the following
events that occurred in one subject each: hyperbilirubinemia,
increased unconjugated blood bilirubin, hypoproteinemia,
hypocalcemia, hematuria, and hyperglycemia. All of these laboratory
parameters were assessed as not related to dexmedetomidine and are
typical of this premature neonate population. Physical examination
data was collected. The most common abnormal findings at screening
and post-dexmedetomidine administration were in the
pulmonary/respiratory system. There were no abnormal, clinically
significant electrocardiogram results at screening, during, or
post-dexmedetomidine administration. Total fluid input ranged from
49.1 to 162.6 mL and total fluid output ranged from 30 to 224 mL.
In general, changes from baseline were not clinically meaningful
for laboratory parameters, vital signs, physical examination, or
electrocardiogram results in the additional cohort.
[0152] Treatment-emergent adverse events were experienced by all 6
subjects in the additional cohort, which are given in Table 9
below. Of the 18 treatment-emergent adverse events reported, only
hypoalbuminemia (n=3) was reported in more than one subject. Most
treatment-emergent adverse events were assessed as not related to
treatment. The only treatment-emergent adverse events that were
assessed as related to dexmedetomidine were mild. One subject
experienced two treatment-emergent adverse events assessed as
related to treatment. One subject experienced three severe
treatment-emergent adverse events; two subjects experienced 1
moderate treatment-emergent adverse event each. None of these
severe or moderate events were assessed as related to
dexmedetomidine. All other events were mild. There were no
treatment-emergent serious adverse events leading to death, one
subject experienced three treatment emergent serious adverse
effects, and no subjects had treatment-emergent adverse events that
led to dexmedetomidine discontinuation. There were no treatment
emergent dose-limiting toxicities that led to dexmedetomidine
discontinuation (persistent bradycardia, persistent hypotension, or
respiratory depression).
TABLE-US-00010 TABLE 9 Summary of Treatment Emergent Adverse Events
by System Organ Class and Preferred Term Dose Level 2 System Organ
Class Preferred Term.sup.(a) Dex 0.1 (N = 6) Number of Events 18
Number of Subjects with at least one event 6 (100.0%) Cardiac
disorders 1 (16.7%) Bradycardia 1 1 (16.7%) Cardio-respiratory
arrest 1 (16.7%) General disorders and administration 2 (33.3%)
site conditions Infusion site extravasation 1 (16.7%) Oedema 1
(16.7%) Hepatobiliary disorders 1 1 (16.7%) Hyperbilirubinaemia 1
(16.7%) Infections and infestations 1 (16.7%) Sepsis 1 (16.7%)
Investigations 2 (33.3%) Blood bilirubin unconjugated increased 1
(16.7%) Oxygen saturation decreased 1 (16.7%) Metabolism and
nutrition disorders 3 (50.0%) Hyperglycaemia 1 (16.7%)
Hypoalbuminaemia 3 (50.0%) Hypocalcaemia 1 (16.7%) Hypoproteinaemia
1 (16.7%) Psychiatric disorders 1 (16.7%) Anger 1 (16.7%) Renal and
urinary disorders 1 (16.7%) Haematuria 1 (16.7%) Note: Percentages
are based on the number of subjects in each dose level and age
group. Subjects are counted once within each system organ class or
for each preferred term and may have had more than one adverse
event. .sup.(a)All investigator adverse event terms were coded
using MedDRA dictionary version 13.0.
[0153] The mean gestational age for group I-level 1 and 2 was 30.3
and 32.5 wks and for group II-levels 1-3, 38.7 wks. Adequate level
of sedation was seen in most patients and rescue sedation with
midazolam (0.22.+-.0.26 mg/kg) was given only in 4 patients (17%)
in group II. Rescue analgesia with fentanyl was given in 2 (17%)
patients in group I, and 11(46%) patients in group II. Additionally
4 (21%) patients in group II received rescue morphine. In group I,
level 1 and 2, dexmedetomidine clearance (CL.sub.w) was 0.41 and
0.29 L/hr/kg, maximum plasma concentration (C.sub.max) was 102 and
107 pg/mL, volume of distribution (V.sub.ssw) was 2.7 and 3.8 L/kg,
and elimination t.sub.1/2 3 and 8 hrs respectively. In group 2,
level 1, 2 and 3 CL.sub.w was 0.61, 0.64 and 0.73 L/hr/kg,
C.sub.max was 78, 122, 325 pg/mL, V.sub.ssw 1.4, 2.8 and 2 L/kg,
and t.sub.1/2 3, 5 and 3 hrs respectively. A lower CL.sub.w was
observed in group I along with a total exposure (AUC) that was 4.5
times larger than group II. The safety profile observed was typical
of the critically ill, high risk pediatric population and
post-operative surgical patients. Adverse events were reported in 8
(67%) patients in group I and 15 (62%) patients in group II but in
only 2 (8%) patients these adverse events were assessed as related
to dexmedetomidine. None had serious adverse events related to
dexmedetomidine or adverse events needing dexmedetomidine
discontinuation.
[0154] The overall efficacy conclusions of the study were not
affected by the update with the additional cohort. Dexmedetomidine
was effective at sedating critically ill, initially intubated and
mechanically ventilated premature infants, .gtoreq.28 to <36
weeks, in the additional cohort and in original 30 patient
population. No subject in the original 30 patient population or the
additional cohort in age group I, dose levels 1 or 2, received
rescue midazolam for sedation during dexmedetomidine infusion. In
the original 30 patient population, at the doses used in this
trial, up to 0.2 .mu.g/kg/hr, dexmedetomidine was effective at
sedating term neonates. In age group II, a total of 4 subjects
(16.7%) received rescue midazolam (mean dose 0.22 mg/kg) for
sedation during dexmedetomidine infusion.
[0155] Most premature neonates in age group I in the additional
cohort and in the interim analyses data did not require additional
medication for pain while on dexmedetomidine infusion. One subject
(16.7%) in each dose level of age group 1 received rescue
medication for analgesia during the study infusion. In contrast, in
the interim analyses, more of the term neonates in age group II
(58.3%) received rescue medication for analgesia during the study
infusion. The increased analgesic requirements in age group II, in
particular dose level 3, most likely reflects the higher proportion
of postoperative surgical subjects.
[0156] Subjects in the additional cohort and in the interim
analyses data spent a low period of time with a total N-PASS
score>3 indicating most subjects were adequately sedated and not
manifesting signs of pain/agitation.
[0157] Lower clearance, higher concentrations, and greater efficacy
were observed in the additional cohort of premature neonates and
consistent with what was observed in the other premature neonate
cohort in the interim analyses compared to the term neonates in the
interim analyses.
[0158] Subjects in the additional cohort of age group I, dose level
2, had a lower median total maintenance dose and duration of
dexmedetomidine exposure compared to age group I, dose level 1 in
the interim analyses. The additional cohort of subjects also had a
lower median total maintenance dose but similar duration of
dexmedetomidine exposure compared to age group II at the same dose
level.
Example 2: Dexmedetomidine Study in Pediatric Intensive Care Unit
Subjects
[0159] A 175-subject, randomized, double-blind, dose-controlled,
multicenter study of dexmedetomidine was conducted on initially
intubated and mechanically ventilated pediatric subjects in the
pediatric intensive care setting. The present study investigated
the efficacy, pharmacokinetics, and safety of dexmedetomidine at
four different dose levels. The subjects were between the ages of 1
month and less than 17 years. For neonates who were born
prematurely, the age was corrected based on gestational age until 3
months of actual birth age. The subjects were mechanically
ventilated prior to and during the commencement of dexmedetomidine,
and were anticipated to require a minimum of 6 hours of continuous
intravenous (IV) sedation. The subjects could be intubated by
nasotracheal, endotracheal or via tracheotomy.
[0160] Subjects also had to have an American Association of
Anesthesiologists (ASA) classification of 1, 2, 3, or 4, and a
University of Michigan Sedation Scale (UMSS) score of 1, 2, 3, or 4
at the start of infusion of dexmedetomidine.
[0161] Subjects were randomized into one of two treatment groups.
Within each treatment group, the loading and maintenance doses were
stratified according to the presence or absence of cardiopulmonary
bypass (CPB). The treatment groups are given in Table 10 below. A
total of 89 subjects were randomized to Group 1 (low dose) and 86
were randomized to Group 2 (high dose). Of these, 83 subjects in
the low dose group and 81 subjects in the high dose received
randomized dexmedetomidine for at least 6 hours.
TABLE-US-00011 TABLE 10 Doses of Dexmedetomidine Diagnosis Group 1
Low dose Group 2 High dose s/p CPB Loading dose: Loading dose 0.2
.mu.g/kg 0.5 .mu.g/kg Maintenance dose titration range Maintenance
dose titration range (0.025-0.5 .mu.g/kg/hr) (0.1-0.7 .mu.g/kg/hr)
All other diagnoses Loading dose Loading dose 0.3 .mu.g/kg 0.6
.mu.g/kg Maintenance dose titration range Maintenance dose
titration range (0.05-0.5 .mu.g/kg/hr) (0.2-1.4 .mu.g/kg/hr)
[0162] The median age of age groups combined was 10.7 months
(range: 0.9 months to 16.3 years) in the low dose group and 14.7
months (range: 1.3 months to 16.2 years) in the high dose group.
Height and weight were similar across dose groups and by underlying
condition (median height of age groups combined: low dose 68.0 cm,
high dose 76.5 cm; median weight of age groups combined: low dose
8.1 kg; high dose 8.5 kg). Slightly more subjects overall were male
than female (low dose, 59.6% male; high dose, 55.8% male).
Demographics were similar between treatment groups with most
subjects critically ill from severe congenital cardiopulmonary
disease (ASA P3).
[0163] Patients were further assigned to age group I or II. The
number of subjects in each subgroup is given in Table 11 below.
TABLE-US-00012 TABLE 11 Number of Subjects in Each Subgroup
(Enrolled Subjects) Group 1 Low Dose Group 2 High Dose s/p
CPB.sup.a Other Dx.sup.b Total s/p CPB.sup.c Other Dx.sup.d Total N
= 36 N = 53 N = 89 N = 37 N = 49 N = 86 Age Group I.sup.e 25 38 63
26 34 60 Age Group II.sup.f 11 15 26 11 15 26 Total 36 53 89 37 49
86 Dx = diagnosis .sup.aDex dose is loading dose (LD) =
0.2/Maintenance dose (MD) = 0.025-0.5 .mu.g/kg/hour .sup.bDex dose
is LD = 0.3/MD = 0.05-0.5 .mu.g/kg/hour .sup.cDex dose is LD =
0.5/MD = 0.1-0.7 .mu.g/kg/hour .sup.dDex dose is LD = 0.6/MD =
0.2-1.4 .mu.g/kg/hour .sup.eAge group I = .gtoreq.1/month to <24
months; .sup.fAge group II = .gtoreq.24 months to <17 years
old
[0164] In age group I, median age was 8.51 months (low dose) and
9.75 months (high dose); in age group II, median age was 6.32 years
(low dose) and 7.57 years (high dose). Subjects had similar
screening ASA classification in both age groups and both
dexmedetomidine dose groups with the majority of subjects having
high risk with severe systemic disease, P3. Subjects who underwent
open-heart surgery were mostly high risk P3 and there were similar
numbers of subjects in the low dose (72.2%) and high dose (73.0%)
dexmedetomidine.
[0165] All subjects (100.0%) in the high dose group and all except
one subject in the low dose group received at least one concomitant
medication during the study; concomitant medication use was similar
across dose groups. Concomitant medications taken by at least 50.0%
of subjects in a dose group, excluding midazolam, fentanyl, and
morphine, the use of which was permitted as rescue medication per
protocol, were furosemide, acetaminophen, potassium chloride, and
heparin. As expected in the s/p CPB groups following open heart
surgery, >90% of subjects were on inotropic support
postoperatively. Inotropic support with milrinone and dobutamine
was similar in both the low and high dose dexmedetomidine groups
s/p CPB.
[0166] Subjects received an optional loading dose of
dexmedetomidine over 10 or 20 minutes followed by the appropriate
maintenance dose. Each subject received a continuous infusion
maintenance dose of dexmedetomidine for a minimum of 6 but not more
than 24 hours.
[0167] The dexmedetomidine administered was a Precedex.RTM.
dexmedetomidine HCl injection manufactured by Hospira, Inc. For
subjects s/p CPB, the low dose dexmedetomidine group was titrated
between 0.025-0.5 .mu.g/kg/hr and the high dose dexmedetomidine
group was titrated between 0.1-0.7 .mu.g/kg/hr; for all other
diagnoses, the low dose dexmedetomidine group was titrated between
0.05-0.5 .mu.g/kg/hr and the high dose dexmedetomidine groups was
titrated between 0.2-1.4 .mu.g/kg/hr. The continuous infusion of
dexmedetomidine was administered for a minimum of 6 and a maximum
duration of 24 hours.
[0168] The dexmedetomidine administered was a Precedex.RTM.
dexmedetomidine HCl injection manufactured by Hospira, Inc.
Dexmedetomidine hydrochloride (HCl) injection (100 .mu.g/mL, base)
was supplied by Hospira to the investigative sites for infusion.
Study medication was prepared (diluted) by the site pharmacy. The
optional loading doses of dexmedetomidine were diluted in 0.9%
sodium chloride or dextrose 5% in water to one of the following
concentrations: 4 .mu.g/mL solution for the high dose group and 2
.mu.g/mL solution for the low dose group. Dexmedetomidine was
infused using a controlled infusion device. The dexmedetomidine
could be administered by a designated IV line for dexmedetomidine
and could also be administered via a designated IV line of
dexmedetomidine attached to a Y-site adapter, or through a
specified side port if given through a central line. No other
medications were to be bolused through the dexmedetomidine infusion
line. The same syringe or bag used for the loading dose could be
used for maintenance--only the rate of infusion changed.
[0169] If rescue midazolam was necessary, the dexmedetomidine dose
was titrated upwards and the need to administer additional
midazolam was reassessed following dexmedetomidine administration.
If rescue pain medication was necessary, then fentanyl or morphine
was administered after the subject was first treated with an
increase in the dexmedetomidine infusion rate, at age-specific
doses, or as a continuous infusion. Subjects receiving continuous
infusions of fentanyl or morphine prior to randomization could
continue these infusions throughout study drug administration if
required.
[0170] Prior to the start of drug infusion, a baseline score on the
UMSS was obtained. The UMSS scale is given in Table 12 below. If a
loading dose was administered, the UMSS score was obtained
immediately before loading and at 5 and 10 minutes during the
loading dose. If the loading dose occurred over 20 minutes, then
the UMSS score was obtained at 15 minutes. If no loading dose was
administered, the UMSS score was obtained at the start of the
maintenance infusion and at 5, 10, 15, 30, and 60 minutes for the
first hour. The UMSS score was obtained every 4 hours during the
remainder of the maintenance infusion. IF rescue medication was
administered, the UMSS score was measured immediately before and 5
minutes after the rescue medication was administered. The UMSS
score was also obtained immediately before and 5 minutes after a
non-pharmacological intervention, such as swaddling, cuddling, or
rocking.
TABLE-US-00013 TABLE 12 University of Michigan Sedation Scale
Clinical Score Level of Sedation 0 Awake/Alert 1 Minimally Sedated:
Tired/sleepy, appropriate response to verbal conversation and/or
sounds. 2 Moderately Sedated: Somnolent/sleeping, easily aroused
with light tactile stimulation. 3 Deeply sedated: Deep sleep,
arousable only with significant physical stimulation. 4
Unarousable
[0171] Chemistry, hematology and urinalysis samples were obtained
for the laboratory tests. A baseline cortisol level test was
conducted prior to the start of dexmedetomidine administration. For
CPB subjects, this blood draw was obtained postoperatively within
90 minutes following the start of dexmedetomidine. An
ACTH-stimulation test were performed at the conclusion of
dexmedetomidine infusion.
[0172] Safety measures included collection of adverse events
(adverse events), heart rate (HR in beats per minute [bpm]),
systolic blood pressure (SBP in millimeters of mercury [mmHg]),
diastolic blood pressure (DBP in millimeters of mercury [mmHg]),
mean arterial pressure (MAP in millimeters of mercury [mmHg]),
oxygen saturation by pulse oximetry (SpO.sub.2 in percentage), and
respiratory rate (RR in breaths/minute [breaths/min]) or ventilator
settings, laboratory results, and electrocardiogram (ECG)
monitoring.
[0173] The statistical analyses were performed using SAS'
Statistical Software System (SAS Institute, Inc., Cary, N.C.),
version 9.1. All statistical tests were 2 sided and p
values.ltoreq.0.0500, after rounding to 4 decimal places, were
considered statistically significant unless otherwise specified. In
general, missing data were not imputed. For continuous variables,
N, mean, median, SD, minimum, Q1, Q3 and maximum are presented. The
mean and median was displayed to 1 decimal place more than the raw
value. The standard deviation (SD) is displayed to 2 decimal places
more than the raw value. For categorical variables, N and percent
is shown. All percentages were reported to 1 decimal place.
[0174] Exposure to dexmedetomidine was highest in the high dose and
generally greater in the other diagnoses group. The average
maintenance dose of dexmedetomidine in pg/kg/hr in the low dose was
0.33 .mu.g/hr/hr with s/p CPB subjects requiring slightly less
maintenance infusion to maintain target sedation. Similarly, in the
high dose dexmedetomidine group the maintenance infusion averaged
0.59 .mu.g/kg/hr, with s/p CPB subjects requiring less maintenance
infusion. The median duration of maintenance infusion was 1215.0
minutes (20.3 hours) for the low dose group and 1127.5 minutes
(18.8 hours) for the high dose group. Median total loading dose was
higher for subjects ASA class P3 and P4 than P1 and P2. The median
total maintenance dose was similar for ASA Class P1 and P2, and P3
and P4 subjects. The median exposure to dexmedetomidine is given in
Table 13 below. The time of exposure is given in Table 14
below.
TABLE-US-00014 TABLE 13 Median Exposure to Study Drug by Time
Points Group 1 Low Dose Group 2 High Dose Median s/p CPB Other Dx
s/p CPB Other Dx Parameter- dexmedetomidine dexmedetomidine
dexmedetomidine dexmedetomidine Age Groups dose dose Total dose
dose Total Combined N = 36 N = 53 N = 89 N =37 N = 49 N = 86
Loading dose N 11 19 30 12 20 32 Total 2.40 2.55 2.48 3.59 4.50
4.14 loading dose (.mu.g) Duration 10.0 10.0 10.0 15.0 17.5 17.5
(min) Loading dose; ASA Class: PI and P2 N 3 7 10 2 7 9 Total 1.70
2.55 2.20 5.75 3.60 3.60 loading dose (.mu.g) Duration 10.0 10.0
10.0 15.0 10.0 10.0 (min) Loading dose; ASA Class: P3 and P4 N 8 12
20 10 13 23 Total 2.78 2.78 2.78 3.38 4.80 4.50 loading dose
(.mu.g) Duration 10.0 10.0 10.0 15.0 20.0 20.0 (min) Maintenance
dose N 36 53 89 37 49 86 Average 0.30 0.35 0.33 0.52 0.67 0.59
maintenance dose (.mu.g/kg/hr) Total 48.67 44.85 45.93 68.60 143.81
76.56 maintenance dose (.mu.g) Duration 1114.5 1380.0 1215.0 840.0
1252.0 1127.5 (min) Maintenance dose: ASA Class P1 and P2 N 9 22 31
5 16 21 Average 0.33 0.35 0.34 0.55 0.64 0.59 maintenance dose
(.mu.g/kg/hr) Total 49.20 52.63 52.14 81.74 162.79 115.21
maintenance dose (.mu.g) Duration 1110.0 1287.5 1215.0 790.0 1374.5
1225.0 (min) Maintenance dose: ASA Class P3 and P4 N 27 31 58 32 33
65 Average 0.30 0.35 0.32 0.51 0.67 0.57 maintenance dose
(.mu.g/kg/hr) Total 48.15 42.39 42.91 59.27 112.75 74.67
maintenance dose (.mu.g) Duration 1119.0 1430.0 1264.0 975.0 1159.0
1120.0 (min)
TABLE-US-00015 TABLE 14 Time of Exposure Group 1 Low Dose Group 2
High Dose Median s/p CPB Other Dx s/p CPB Other Dx Parameter-
dexmedetomidine dexmedetomidine dexmedetomidine dexmedetomidine Age
Groups dose dose Total dose dose Total Combined N = 36 N = 53 N =
89 N = 37 N = 49 N = 86 Time of exposure <1 hour N 1 1 Total --
-- -- -- 7.25 7.25 dose (.mu.g) 47.0 47.0 Time of exposure >1
hour N 36 53 89 37 48 85 Average 0.30 0.35 0.33 0.52 0.67 0.59
maintenance dose (.mu.g/kg/hr) Total 48.67 46.31 46.85 68.60 146.90
79.44 dose (.mu.g) Duration 1121.0 1390.0 1215.0 848.0 1288.5
1133.0 (min) Time of exposure >6 hours N 31 49 80 30 45 75
Average 0.31 0.35 0.33 0.52 0.67 0.59 maintenance dose
(.mu.g/kg/hr) Total 50.69 51.49 50.97 78.49 172.80 88.26
maintenance dose .mu.g) Duration 1160.0 1415.0 1343.5 1050.5 1320.0
1170.0 (min) Time of exposure >12 hours N 26 39 65 23 41 64
Average 0.31 0.35 0.33 0.54 0.66 0.60 maintenance dose
(.mu.g/kg/hr) Total 53.67 59.71 56.09 86.24 172.80 112.82
maintenance dose .mu.g) Duration 1307.5 1439.0 1411.0 1142.0 1395.0
1266.0 (min) Time of exposure 0-6 hours N 5 4 9 7 4 11 Average 0.23
0.39 0.30 0.49 0.63 0.56 maintenance dose (.mu.g/kg/hr) Total 11.99
9.31 11.16 25.67 30.16 28.57 dose (.mu.g) Duration 357.0 147.5
353.0 360.0 305.0 360.0 (min) Time of exposure >6-12 hours N 5
10 15 7 4 11 Average 0.33 0.34 0.33 0.50 0.96 0.56 maintenance dose
(.mu.g/kg/hr) Total 25.90 41.49 36.55 31.59 106.61 34.19 dose
(.mu.g) Duration 470.0 438.0 466.0 533.0 542.5 533.0 (min)
[0175] Overall the high dose dexmedetomidine group was clinically
better sedated than the low dose dexmedetomidine groups with 54.3%
of high dose subjects not requiring rescue midazolam compared to
44.6% in the low dose dexmedetomidine groups, although this was not
statistically significant (p=0.2751). By age, a smaller percentage
of subjects in age group II did not require rescue midazolam for
sedation in comparison with age group I in both dexmedetomidine
dose groups; this difference was not statistically significant
(p=0.6723). In both dose groups subjects undergoing open heart
surgery with CPB received more rescue midazolam than those in the
other diagnoses groups. The greatest difference between treatment
groups was in the heart surgery subjects with more subjects in both
age groups receiving high dose dexmedetomidine than low dose
dexmedetomidine and not requiring midazolam sedation rescue. The
difference was 22.73%, although it was not statistically
significant (p=0.0974). Table 15 contains number and percent of
subjects who did not require midazolam for sedation during
treatment. Table 16 contains the differences between treatment
groups in percentage of subjects who did not require midazolam for
sedation during treatment.
TABLE-US-00016 TABLE 15 Number and Percent of Subjects Who Did Not
Require Rescue Midazolam for Sedation During the Treatment Period
While Intubated s/p CPB Other Dx s/p CPB Other Dx Number and
dexmede- dexmede- dexmede- dexmede- Percent of tomidine tomidine
tomidine tomidine Subjects.sup.a dose dose Total dose dose Total
Total ASA Class N = 33 N = 50 N = 83 N = 34 N = 47 N = 81 Age Group
I.sup.b 5 (15.2) 20 (40.0) 25 (30.1) 10 (29.4) 20 (42.6) 30 (37.0)
Age Group II.sup.c 4 (12.1) 8 (16.0) 12 (14.5) 7 (20.6) 7 (14.9) 14
(17.3) Total 9 (27.3) 28 (56.0) 37 (44.6) 17 (50.0) 27 (57.4) 44
(54.3) ASA Class: P1, P2 N = 8 N = 21 N = 29 N = 5 N = 16 N = 21
Age Group I.sup.b 1 (12.5) 8 (38.1) 9 (31.0) 1 (20.0) 7 (43.8) 8
(38.1) Age Group II.sup.c 0 4 (19.0) 4 (13.8) 0 2 (12.5) 2 (9.5)
Total 1 (12.5) 12 (57.1) 13 (44.8) 1 (20.0) 9 (56.3) 10 (47.6) ASA
Class: P3, P4 N = 25 N = 29 N = 54 N = 29 N = 31 N = 60 Age Group
I.sup.b 4 (16.0) 12 (41.4) 16 (29.6) 9 (31.0) 13 (41.9) 22 (36.7)
Age Group II.sup.c 4 (16.0) 4 (13.8) 8 (14.8) 7 (24.1) 5 (16.1) 12
(20.0) Total 8 (32.0) 16 (55.2) 24 (44.4) 16 (55.2) 18 (58.1) 34
(56.7) .sup.aNumber and percent of subjects who did not require
rescue midazolam for sedation based on achieving and maintaining a
target UMSS range of 1 to 3 while intubated. .sup.bAge group I =
.gtoreq.1 month to <24 months .sup.cAge group II = .gtoreq.24
months to <17 years old
TABLE-US-00017 TABLE 16 Differences Between Treatment Groups in
Percentage of Subjects who did not Require midazolam for Sedation
During the Treatment Period While Intubated Underlying Condition/
Group 1 Low Group 2 High Difference p- Age Group Dose Dose (Group
1-2).sup.b value.sup.c Total ASA Class All Diagnoses 37/83 (44.6)
44/81 (54.3) -9.74 0.2751 [n (%)].sup.a Age Group I.sup.d 25/57
(43.9) 30/56 (53.6) -9.71 0.3984 Age Group II.sup.e 12/26 (46.2)
14/25 (56.0) -9.85 0.6723 s/p CPB [n (%)] 9/33 (27.3) 17/34 (50.0)
-22.73 0.0974 Age Group I.sup.d 5/22 (22.7) 10/23 (43.5) -20.75
0.2461 Age Group II.sup.e 4/11 (36.4) 7/11 (63.6) -27.27 0.3938
Other Diagnoses 28/50 (56.0%) 27/47 (57.4%) -1.45 1.0000 [n (%)]
Age Group I.sup.d 20/35 (57.1) 20/33 (60.6) -3.46 0.9653 Age Group
II.sup.e 8/15 (53.3) 7/14 (50.0) 3.33 1.0000 ASA Class: P1, P2 All
Diagnoses 13/29 (44.8) 10/21 (47.6) -2.79 1.0000 [n (%)].sup.a Age
Group I.sup.d 9/19 (47.4) 8/15 (53.3) -5.96 1.0000 Age Group
II.sup.e 4/10 (40.0) 2/6 (33.3) 6.67 1.0000 s/p CPB [n (%)] 1/8
(12.5) 1/5 (20.0) -7.50 1.0000 Age Group I.sup.d 1/6 (16.7) 1/3
(33.3) -16.67 1.0000 Age Group II.sup.e 0/2 0/2 0.00 -- Other
Diagnoses 12/21 (57.1) 9/16 (56.3) 0.89 1.0000 [n (%)] Age Group
I.sup.d 8/13 (61.5) 7/12 (58.3) 3.21 1.0000 Age Group II.sup.e 4/8
(50.0) 2/4 (50.0) 0.00 1.0000 ASA Class: P3, P4 All Diagnoses 24/54
(44.4) 34/60 (56.7) -12.22 0.2645 [n (%)].sup.a Age Group I.sup.d
16/38 (42.1) 22/41 (53.7) -11.55 0.4228 Age Group II.sup.e 8/16
(50.0) 12/19 (63.2) -13.16 0.6594 s/p CPB [n (%)] 8/25 (32.0) 16/29
(55.2) -23.17 0.1515 Age Group I.sup.d 4/16 (25.0) 9/20 (45.0)
-20.00 0.3722 Age Group II.sup.e 4/9 (44.4) 7/9 (77.8) -33.33
0.3336 Other Diagnoses 16/29 (55.2) 18/31 (58.1) -2.89 1.0000 [n
(%)] Age Group I.sup.d 12/22 (54.5) 13/21 (61.9) -7.36 0.8573 Age
Group II.sup.e 4/7 (57.1) 5/10 (50.0) 7.14 1.0000 .sup.aSubjects
who did not require rescue midazolam for sedation based on
achieving and maintaining a target UMSS range 1-3 while intubated.
.sup.bMean difference between treatment groups in percentage of
subjects who did not require rescue midazolam for sedation based on
achieving and maintaining a target UMSS of 1-3 while intubated.
.sup.cP-value for risk difference for 2 .times. 2 table from
Chi-Square test with continuity correction. .sup.dAge group I =
.gtoreq. 1 month to < 24 months .sup.eAge group II = .gtoreq. 24
months to < 17 years old
[0176] All age groups and diagnoses receiving the high dose of
dexmedetomidine were in the targeted UMSS range 87.8 to 99.2% of
the time compared to 85.5 to 99.0% of the time in the low dose
dexmedetomidine groups. There were no statistical differences
between dexmedetomidine dose groups in the absolute time or
percentage of time subjects were in the target sedation range (UMSS
1-3). All age groups and diagnoses receiving the low dose of
dexmedetomidine were out of the target UMSS range 1.0 to 14.5% of
the time compared to 0.8 to 12.2% of the time in the high dose
dexmedetomidine groups. There were no statistical differences
between dexmedetomidine dose groups in the absolute time or
percentage of time subjects were out of the target sedation range
(UMSS<1 or >3).
[0177] Overall, more rescue midazolam for sedation (total dose and
dose/kg) was required in the low dose dexmedetomidine groups than
the high dose dexmedetomidine groups, although the differences were
not statistically significant. With the age groups combined, 46/83
subjects (55.4%) in the low dose dexmedetomidine group required
rescue midazolam for sedation compared with 37/81 subjects (45.7%)
in the high dose dexmedetomidine group. Median total amount of
rescue midazolam required for sedation while intubated during the
treatment period for the subjects that required rescue midazolam
for sedation was 1.965 mg (range: 0.19-30.80 mg) in the low dose
group and 2.00 mg [range: 0.10-13.20 mg]) the high dose group; and
median amount of rescue midazolam per kg was 0.266 mg/kg (range:
0.02-1.49 mg/kg) in the low dose group and 0.179 mg/kg (range:
0.02-1.11 mg/kg) in the high dose group. Results were similar by
age group.
[0178] With the age groups combined, 53/83 subjects (63.9%) in the
low dose dexmedetomidine group and 44/81 subjects (54.3%) in the
dexmedetomidine high dose dexmedetomidine group received rescue
fentanyl for analgesia while intubated during the treatment period.
Median total amount of rescue fentanyl required for analgesia for
the subjects who required rescue fentanyl was 46.00 .mu.g (range:
1.50-593.00 .mu.g) in the low dose group and 35.13 .mu.g (range:
1.50-750.00 .mu.g) in the high dose; and median amount per kg of
rescue fentanyl required for analgesia was 4.13 .mu.g/kg (range:
0.10-83.52 .mu.g/kg) in the low dose group and 3.25 .mu.g/kg
(range: 0.08-35.98 .mu.g/kg) in the high dose group.
[0179] With the age groups combined, 35/83 subjects (42.2%) in the
low dose group and 32/81 subjects (39.5%) in the dexmedetomidine
high dose group received rescue morphine for analgesia while
intubated during the treatment period. Median total amount of
rescue morphine required for analgesia for the subjects who
required rescue morphine was 1.80 mg (range: 0.25-20.50 mg) in the
low dose dexmedetomidine group and 1.63 mg (range: 0.32-15.00 mg)
in the high dose dexmedetomidine group; and median amount of rescue
morphine per kg was 0.20 mg/kg (range: 0.03-4.10 mg/kg) in the low
dose dexmedetomidine group and 0.17 mg/kg (range: 0.05-0.57 mg/kg)
in the high dose dexmedetomidine group. Difference in time to first
rescue medication was not statistically significant; median time
from start of dexmedetomidine infusion to first dose of rescue
medication was 1.6 hours (95% CI: 0.93, 3.38) in the low dose
dexmedetomidine group and 2.0 hours (95% CI: 1.07, 3.75) in the
high dose group.
[0180] The time to extubation was estimated from the first
termination of mechanical ventilation within the dexmedetomidine
infusion period until the 24-hour follow-up. If the subject's
ventilator setting was not available, and dexmedetomidine was
discontinued because it was no longer required for sedation,
extubation time was estimated as the end of dexmedetomidine
date/time. Subjects with no measurable time to extubation as
described above were excluded from analysis. If extubation was
successful, the subject was considered to have the event. Subjects
who were not extubated were censored; time of censoring was set to
the time of the subject's last observation during the corresponding
evaluable period and might represent time of subject's withdrawal
from the study, time of death, or the time of the last recorded
observation during the evaluable period, whichever happened first.
Median time to successful extubation was 23.8 hours (95% CI: 18.55,
N/A) in the low dose dexmedetomidine group and 20.5 hours (95% CI:
17.13, 23.33) in the high dose dexmedetomidine group; the
difference was not statistically significant.
[0181] In general, moderate or severe adverse events were more
common in the low dose than high dose dexmedetomidine groups and
there were more actual events reported in age group I than age
group II: in age group I, moderate and severe treatment-related
adverse events were experienced by 17 (27.0%; 30 events) and 10
subjects (16.7%; 17 events) in the low and high dose groups,
respectively; and in age group II, moderate and severe
treatment-related adverse events were experienced by 8 (30.8%; 13
events) and 6 subjects (23.1%; 9 events) in the low and high dose
groups, respectively. Overall, 5/175 subjects (2.9%) reported a
total of seven severe treatment-related adverse events; all severe
treatment-related adverse events were reported in the low dose
dexmedetomidine groups. The severe treatment-related adverse events
reported were myocarditis, pyrexia, status epilepticus, dyspnea,
ventricular fibrillation, chest pain, and wheezing. The severe
myocarditis event was also considered a serious treatment-related
adverse event.
[0182] Treatment-related adverse events experienced by 2 or more
subjects in a dose group in age group I were hypotension (3
subjects [4.8%] and 5 subjects [8.3%], in the low and high dose
dexmedetomidine groups, respectively), agitation (2 [3.2%] and 4
[6.7%]), and bradycardia (2 [3.2%] and 2 [3.3%]), and hypertension
(2 [3.2%] in the low dose dexmedetomidine group); and in age group
II, hypotension (2 subjects [7.7%] in the high dose group).
[0183] Serious treatment-related adverse events and
treatment-related adverse events that led to dexmedetomidine or
study discontinuation were only reported in age group I. Two
serious treatment-related adverse events were reported in this
study, myocarditis (1 subject, low dose) and apnea (1 subject, high
dose); both events were considered possibly or probably related to
dexmedetomidine. Seven subjects (4.0%) experienced a total of 8
treatment-related adverse events that led to discontinuation of
dexmedetomidine (respiratory rate decreased and respiratory
acidosis [each 1 subject, low dose] and bradycardia, device
electrical finding, endotracheal intubation complication,
agitation, apnea, hypotension [each 1 subject, high dose]). Two
subjects experienced treatment-related adverse events that led to
study discontinuation (oxygen saturation decreased and agitation [1
subject, high dose] and hypotension [1 subject, low dose]). There
were 4 deaths, all unrelated to dexmedetomidine. No subjects
stopped dexmedetomidine due to death.
[0184] Whereas the median amount (total and per kg) of rescue
midazolam for sedation and rescue fentanyl and morphine was not
statistically significantly different between the low and high dose
dexmedetomidine groups, total and per/kg doses of rescue midazolam
for sedation, rescue fentanyl for analgesia, and rescue morphine
for analgesia trended higher in the low dose dexmedetomidine
group.
[0185] The study demonstrates that dexmedetomidine was clinically
effective at sedating critically ill, initially intubated infants
and children following major cardiac surgery with CPB and
non-cardiac surgery. There was a non-significant (p=0.2751)
dose-response effect observed with more subjects (54.3%) in the
high dose dexmedetomidine groups not requiring rescue midazolam to
maintain the target sedation than in the low dose dexmedetomidine
groups (44.6%), irrespective of age. High dose dexmedetomidine was
most effective in the heart surgery subjects (s/p CPB) with more
subjects of both age groups who received high dose dexmedetomidine
than low dose dexmedetomidine not requiring midazolam sedation
rescue (p=0.0974, difference=22.73%). All age groups and diagnoses
receiving the high dose of dexmedetomidine were in the target UMSS
range (1-3) 87.8 to 99.2% of the time compared to 85.5 to 99.0% of
the time in the low dose dexmedetomidine groups; the difference was
not statistically significant.
Example 3: Pharmacokinetics of Dexmedetomidine in Pediatric
Patients
[0186] The present study characterizes the pharmacokinetic and
pharmacodynamic profile of dexmedetomidine administered as an
intravenous (IV) loading dose followed by a continuous IV infusion
in pediatric subjects.
[0187] A 56-subject, open-label, multicenter, escalating dose study
of dexmedetomidine was conducted on initially intubated and
mechanically ventilated pediatric subjects who required sedation in
an intensive care setting and was anticipated to require a minimum
of 6 hours but not to exceed 24 hours of continuous IV sedation.
The present study investigated the pharmacokinetics and
pharmacodynamics of dexmedetomidine. The subjects were at least 2
years old and less than 17 years old.
[0188] The subjects were separated into two age groups. Group I
consisted of children who were at least 2 years old and younger
than 6 years old and Group II consisted of children who were at
least 6 years old and younger than 17 years old. Within each group
there were four escalating dosing levels (Table 17). The subject
disposition and demographics of the study are described in Table
18.
[0189] A total of 69 subjects were enrolled into the study. Of
those, 59 received dexmedetomidine (any amount) and were included
in the safety population (26 in Group I, 33 in Group II).
[0190] A total of 56 subjects completed the study, 26 in Group I
and 30 in Group II. Three patients from Group II were prematurely
discontinued from the study due to protocol deviations (1 subject
each from Dose Levels 1, 2 and 3).
[0191] The full evaluable population consisted of 57 subjects who
received the study drug infusion for at least 5 hours (26 in Group
I, 31 in Group II). Two subjects from Group II were excluded from
the full evaluable population.
[0192] Subjects in Group I were primarily male (57.7%) and White
(88.5%) with a mean (SD) age of 3.7 (1.12) years. Subjects in Group
II were primarily female (63.6%) and White (72.7%) with a mean (SD)
age of 10.3 (3.24) years, as shown in Table 18.
TABLE-US-00018 TABLE 17 Study Design Group I Maintenance (Ages
.gtoreq. 2 Infusion through < 6 years old) Loading (at least 6
Post- Group II (Ages .gtoreq. 6 Dose hours and Treatment through
< 17 years old) (10 minutes) up to 24 hours) Period Level 1 0.25
.mu.g/kg 0.2 .mu.g/kg/hr 24 hours Level 2 0.50 .mu.g/kg 0.4
.mu.g/kg/hr 24 hours Level 3 1.00 .mu.g/kg 0.7 .mu.g/kg/hr 24 hours
Level 4 1.00 .mu.g/kg 2.0 .mu.g/kg/hr 24 hours Abbreviations: DEX =
dexmedetomidine
TABLE-US-00019 TABLE 18 Subject Demographics-Safety Population
Group I Group II Dose Dose Dose Dose Dose Dose Dose Dose
Characteristic Level 1 Level 2 Level 3 Level 4 Level 1 Level 2
Level 3 Level 4 Mean (SD) (N = 8) (N = 6) (N = 6) (N = 6) (N = 8)
(N = 8) (N = 9) (N = 8) Age (years) 3.4 3.6 4.3 3.6 9.3 10.4 11.1
10.4 (1.03) (0.98) (1.50) (0.96) (2.23) (3.99) (3.64) (3.15) % Male
50.0 50.0 66.7 66.7 25.0 37.5 22.2 62.5 % White 87.5 100.0 83.3
83.3 62.5 75.0 88.9 62.5 Weight (kg) 14.6 13.8 16.5 13.7 40.5 32.6
37.1 38.5 (3.02) (3.55) (4.55) (1.75) (28.65) (17.42) (24.42)
(19.36) Height (cm) 96.6 94.8 101.5 101.2 131.8 133 6 132.4 138.1
(6.35) (10.42) (10.31) (12.64) (17.71) (23.57) (18.99) (25.52)
Abbreviations: DEX = dexmedetomidine
[0193] The dexmedetomidine administered to the subjects was a
Precedex.RTM. dexmedetomidine HCl injection (manufactured and
supplied by Hospira, Inc.). Dexmedetomidine hydrochloride (HCl)
injection (100 .mu.g/mL, base) was supplied to the investigative
sites for infusion. Study medication was prepared (diluted) by the
site pharmacy to 4 .mu.g/mL in 0.9% sodium chloride and was not
refrigerated. The dexmedetomidine was administered as a two-stage
IV infusion using a controlled infusion device through a designated
IV line, but never directly into the pulmonary artery.
[0194] Dexmedetomidine was administered as a two-stage IV infusion
with a loading dose infusion for 10 minutes and was immediately
followed by a continuous fixed maintenance dose for a minimum of 6
to a maximum of 24 hours, at four increasing dose levels. Each dose
increase was dependent on the tolerability of the previous dose.
After the subjects completed the dexmedetomidine maintenance
infusion, the post-infusion procedures were initiated and continued
for 24 hours.
[0195] The primary evaluation was the estimation of dexmedetomidine
pharmacokinetic parameters for each age group by dose level
including AUC (area under the plasma concentration-time curve),
C.sub.max (observed peak plasma concentration), C.sub.ss (steady
state concentration), CL (plasma clearance), V.sub.s, (volume of
steady state distribution) and t.sub.1/2 (terminal half-life).
[0196] Safety monitoring included treatment emergent adverse events
(TEAEs) (severity, relationship to study drug), vital signs,
clinical laboratory results and electrocardiogram (ECG) and
physical exam finding.
[0197] The dexmedetomidine infusion began after discontinuation of
all other sedative and analgesic agents and the subject attained a
Ramsay Sedation Scale (RSS) of 2, 3, or 4. The RSS is a clinically
derived scale used to quantify depth of anesthesia and has been
used in children ranging in age from 1 month to 18 years old. The
RSS scale is given in Table 19 below. Rescue medication (midazolam
or fentanyl) was administered as needed for sedation and pain,
respectively, during study drug administration based on results of
the sedation (RSS) and pain (Face, Legs, Activity, Cry, and
Consolability [FLACC]) scales. After the discontinuation of
dexmedetomidine infusion, further sedation and analgesia was
provided per standard of care.
TABLE-US-00020 TABLE 19 Ramsay Sedation Scale Clinical Score Level
of Sedation 1 Patient is anxious and agitated or restless, or both.
2 Patient is cooperative, orientated and tranquil. 3 Patient
responds to command only. 4 Patient exhibits brisk response to
light glabellar (between the eyebrows) tap or loud auditory
stimulus. 5 Patient exhibits a sluggish response to light glabellar
tap or loud auditory stimulus. 6 Patient exhibits no response to
stimulus.
[0198] The level of sedation was assessed first using the RSS and
then the Richmond Agitation Sedation Scale (RASS) immediately after
completion of the RSS. The RASS has been used and validated to
quantify depth of anesthesia in adults in the ICU setting; however
it has not been validated in infants and children. The purpose of
using the RASS in this study was to evaluate the suitability of the
RASS in children who were 2 years old to younger than 17 years old.
The RASS scale is given in Table 20 below.
TABLE-US-00021 TABLE 20 Richmond Agitation Sedation Scale (RASS)
Score Term Description +4 Combative Overtly combative, violent,
immediate danger to staff +3 Very agitated Pulls or removes tube(s)
or catheter(s); aggressive +2 Agitated Frequent non-purposeful
movement, fights ventilator +1 Restless Anxious but movements not
aggressive, vigorous 0 Alert and calm -1 Drowsy Not fully alert,
but has sustained awakening (eye-opening/eye contact) to voice
(>10 seconds) -2 Light Sedation Briefly awakens with eye contact
to voice (<10 seconds) -3 Moderate Sedation Movement or eye
opening to voice (but no eye contact) -4 Deep Sedation No response
to voice, but movement or eye opening to physical stimulation. -5
Unarousable No response to voice or physical stimulation
[0199] Based on the RSS and RASS scores and clinical judgment,
additional rescue sedation with IV midazolam was administered if
subjects were not completely sedated. For subjects 6 months to 5
years old, the midazolam dose was 0.05 to 0.1 mg/kg. For subjects 6
to 12 years old, the midazolam dose was 0.025 to 0.05 mg/kg.
Subjects who were older than 12 years were administered 1 mg/kg of
midazolam.
[0200] Pain was assessed using the Faces, Legs, Activity, Cry, and
Consolability (FLACC) scale. The FLACC scale is a valid and
reliable observational tool used as a measure of pain in children
ranging in age from 2 months to 18 years old. The FLACC scale is
given in Table 21 below.
TABLE-US-00022 TABLE 21 Faces, Legs, Activity, Cry, and
Consolability Scale Scoring Category 0 1 2 Face No particular
expression Occasional grimace or Frequent to constant or smile
frown, withdrawn, quivering chin, clenched disinterested jaw Legs
Normal position or Uneasy, restless, tense Kicking, or legs drawn
relaxed up Activity Lying quietly, normal Squirming, shifting back
Arched, rigid, or jerking position, moves easily and forth, tense
Cry No cry (awake or asleep) Moans or whimpers; Crying steadily,
screams occasional complaint or sobs, frequent complaints
Consolability Content, relaxed Reassured by occasional Difficult to
console or touching, hugging or comfort being talked to,
distractible
[0201] Rescue fentanyl IV was administered at the recommended dose
of 0.25 to 1 .mu.g/kg as needed to treat pain based on clinical
judgment or FLACC scores greater than 4 while receiving
dexmedetomidine infusion. FLACC scores were documented before and
within five minutes after the administration of any rescue
fentanyl. Each of the five FLACC scale categories was scored from 0
to 2, which resulted in a total score between zero and ten.
[0202] Prior medications, defined as medications taken within 48
hours prior to the start of study drug infusion, were taken by
96.6% of the study subjects. The most frequently used prior
medications reported for use by subjects were from the nervous
system (94.9%), alimentary tract and metabolism (83.1%), and
musculoskeletal system (79.7%) drug classes and included the
following: fentanyl citrate (81.4%), midazolam (66.1%), magnesium
sulfate (28.8%), ranitidine (28.8%), and vecuronium (27.1%).
[0203] Concomitant medications were defined as infusion and
noninfusion medications received during the study drug infusion
period through the post-study drug administration period.
Concomitant noninfusion medications were taken by all subjects
(100%) and infusion medications were taken by 39.0% of subjects in
the enrolled population. The most frequently used concomitant
noninfusion medications reported were from the nervous system
(100%), alimentary tract and metabolism (98.3%), and antiinfectives
for systemic use (96.6%) drug class and included the following:
fentanyl citrate (88.1%), midazolam (67.8%), magnesium sulfate
(35.6%), and cephalothin (32.2%). The most frequently used
concomitant infusion medications reported were from the
cardiovascular system (30.5%), blood and blood forming organs
(28.8%), nervous system (23.7%), and alimentary tract and
metabolism (22.0%) drug class and included the following: milrinone
(23.7%), papaverine (20.3%), heparin (18.6%), fentanyl citrate
(6.8%), and midazolam (5.1%).
[0204] Subjects receiving continuous IV infusions of fentanyl were
able to have these infusions re-started after starting the
dexmedetomidine infusion. Subjects who were receiving continuous
infusions of fentanyl had FLACC scores recorded immediately before
and within five minutes after any change in the dose of the
fentanyl infusion.
[0205] The subjects had to be initially intubated when starting the
dexmedetomidine treatment. Once subjects had met site-specified
respiratory criteria, they could undergo tracheal extubation, at
any time following the start of the loading dose. The
dexmedetomidine infusion could be continued during and after the
extubation process. Sedation levels and vital signs were monitored
and recorded in the peri-extubation period.
[0206] The pharmacodynamic and safety measures monitored included:
sedation levels (by RSS and RASS scores), heart rate (HR), blood
pressure (BP), respiratory rate (RR), and oxygen saturation by
pulse oximetry (SpO.sub.2). The BP, HR, SpO.sub.2, and RR were
recorded prior to the loading dose, at 5 and 10 minutes during the
load, and hourly during the maintenance infusion, as close as
possible (up to 5 minutes prior) to the scheduled pharmacokinetic
sampling times, and concurrent with the RSS, RASS, and the FLACC
scale. Cardiac monitoring was continuous. A 12-lead ECG was
obtained after five hours of maintenance infusion but before
discontinuing the infusion. After discontinuing the infusion, HR,
BP, RR, and SpO.sub.2 were recorded every 15 minutes for the first
hour, every 30 minutes for 2 hours, every hour for 3 hours and then
every 4 hours until last pharmacokinetic sample was obtained. Vital
signs were obtained in conjunction with the pharmacokinetic
samples, up to five minutes prior.
[0207] The dexmedetomidine infusion rate was not titrated during
this trial. After the discontinuation of the dexmedetomidine
infusion, further sedation and analgesia may have been provided per
standard of care; however, dexmedetomidine was not restarted until
after the last pharmacokinetic sample was obtained.
[0208] Venous or arterial blood samples were collected for
determination of plasma dexmedetomidine concentrations. Blood
samples were collected via a peripheral venous, central venous,
peripherally inserted central venous catheter (PICC) or arterial
line into heparinized vacutainer tubes for pharmacokinetic
analysis. An arterial line must have already been in place as part
of the standard of care in order to have been used for sample
collection. In no case was an arterial line placed for the sole
reason of collection of pharmacokinetic samples. Additionally, all
pharmacokinetic samples were drawn consistently from either a
venous or an arterial access for the duration of the study;
interchangeability between venous and arterial draws was not
allowed. Blood samples were collected at each of the following time
points: no more than 30 minutes prior to the start of the loading
dose; within five minutes before the loading dose was finished and
simultaneous with the start of the maintenance infusion; 0.5, 1, 2
and 4 to 6 hours after the start of maintenance infusion; within 30
minutes prior to the end of maintenance infusion, which must have
been within 24 hours of start of maintenance infusion; ten minutes
after the maintenance infusion had ended; and 0.5, 1, 2, 4 and 10
hours after the maintenance infusion had ended.
[0209] For pharmacokinetic analyses, venous blood samples (1 mL)
were collected in heparinized tubes at a site opposite from the
site of infusion (e.g., left arm vs. right arm). Samples were not
drawn from the second lumen of a multi-lumen catheter through which
drug was being administered. If arterial blood samples (1 mL) were
collected, heparinized tubes were also used.
[0210] The pharmacokinetic analysis was performed using model
independent methods. The primary evaluation was the assessment of
dexmedetomidine pharmacokinetics on the full evaluable population.
As used herein, the term "full evaluable population" refers to the
pediatric subjects who received at least 5 hours of dexmedetomidine
infusion. As used herein, the term "safety population" refers to
the pediatric subjects who received any amount of
dexmedetomidine.
[0211] Pharmacokinetic parameters were estimated by
non-compartmental methods. Parameters estimated included: AUC (area
under the plasma concentration-time curve), C.sub.max (observed
peak plasma concentration), CL (plasma clearance), C.sub.ss (steady
state concentration), V.sub.ss (volume of steady state
distribution), and t.sub.1/2 (terminal half-life).
[0212] Additional parameters were determined as deemed appropriate.
Plasma concentrations and resultant pharmacokinetic parameters were
summarized by descriptive statistics, number of subjects,
arithmetic mean, SD, coefficient of variation (CV), median, and
range (minimum and maximum).
[0213] An assessment of dose proportionality was made for AUC and
C.sub.max among the dose levels administered. The Power Analysis
approach and data visualization techniques were used for this
assessment.
[0214] The primary evaluation was the assessment of dexmedetomidine
pharmacokinetics. The pharmacokinetic analyses were summarized for
each age group by dose level for the full evaluable population, as
a primary analysis. Data from all full evaluable subjects were
included in the analysis. The pharmacokinetic parameters were
estimated by non-compartmental methods. Summary statistics for the
pharmacokinetic parameters were tabulated. Only subjects with
sufficient pharmacokinetic and pharmacodynamic data to calculate
the pharmacokinetic and pharmacodynamic parameters were included in
the analysis population.
[0215] In order to identify pharmacokinetic variation among
different dosing levels and different age groups, plots of mean
plasma dexmedetomidine concentrations vs. time curve during the
study drug infusion period and post-study drug infusion by dose
level were produced for each age group. An overlay plot of
individual plasma dexmedetomidine concentrations vs. time by dose
level was generated. Descriptive statistics of C.sub.ss, C.sub.max,
V.sub.ss, CL, AUC, t.sub.1/2, time of maximum concentration
(t.sub.max), terminal elimination rate constant (.lamda.z), volume
of distribution (V.sub.d), and weight-adjusted CL and V.sub.d were
summarized by dose level for each age group. Within each dose
level, a 2-sample t-test was used to assess the difference of these
pharmacokinetic parameters between age groups. The overall dose
level by age group was assessed with a 2-way analysis of variance.
In addition, V.sub.ss and CL were also summarized by pooling data
from all dose levels within each age group, and a 2-sample t-test
was used to assess the difference between age groups.
[0216] Scatter plots of V.sub.ss and CL vs. age (yrs) and V.sub.ss
and CL vs. weight (kg) were visually produced with data pooled from
all dose levels and age groups. The association between these
pharmacokinetic parameters, adjusted for weight or dose, was
assessed by linear or non-linear regression analysis based on the
results from the dose proportionality analysis.
[0217] The pharmacodynamic analyses were summarized for each age
group by dose level for the full evaluable population, as a primary
analysis, and for the safety population, as a secondary analysis.
The following descriptive statistics were summarized by dose level
for each age group: RSS.sub.5, RSS.sub.avg, N (%) of subjects who
received rescue midazolam, time to first use of rescue midazolam,
total amount of rescue midazolam, N (%) of subjects who received
rescue fentanyl, total amount of rescue fentanyl, N (%) of subjects
who were converted to alternative sedative or analgesic therapy,
time to successful extubation, and change from baseline in mean,
maximum, and minimum values of HR, SBP, DBP, MAP, RR, SpO.sub.2
during infusion and post-infusion. As used herein, the term
"baseline" refers to just prior to loading of dexmedetomidine.
[0218] The following descriptive statistics were also summarized,
respectively, for subjects who received dexmedetomidine alone and
for subjects who received dexmedetomidine with co-administration of
midazolam or fentanyl: RSS.sub.5, RSS.sub.avg, N (%) of subjects
who were converted to alternative sedative or analgesic therapy,
time to extubation, change from baseline in mean, max, and min
values of HR, SBP, DBP, MAP, RR, SpO.sub.2 during infusion and
post-infusion. These analyses were performed for each age group by
pooling data from all dose levels within the age group.
[0219] In addition, the time to the first rescue medication for
sedation and the time to successful extubation were assessed with
the Kaplan-Meier method. Treatment group comparison and/or subjects
who received dexmedetomidine alone and subjects who received
dexmedetomidine with co-administration of midazolam or fentanyl for
successful extubation were then assessed with log-rank and Wilcoxon
tests.
[0220] The relationship between the level of sedation and plasma
concentration, supplemental sedation requirements, and impact of
dexmedetomidine alone, and with co-administration of midazolam or
fentanyl, on sedation, HR, and BP was analyzed. Subsequent
pharmacokinetic and pharmacodynamic relationships and modeling were
done to identify covariates that may further explain
inter-individual variability in the pharmacokinetic and
pharmacodynamic parameters.
[0221] The statistical analyses, summary tables, and data listings
were performed or prepared using SAS.RTM. software, Version 9.1.
Pharmacokinetic parameters were calculated using the computer
program WinNonlin (Version 5.1 or higher--PharSight, Mountainview,
Calif.).
[0222] Summaries of the percentages of subjects stratified by dose
level and age group who were intubated and simultaneously received
rescue midazolam for sedation during the treatment period are
presented in Table 22 for the full evaluable population. A summary
of the weight-adjusted total amount of rescue medication
(midazolam, fentanyl) required for sedation and analgesia while
intubated during the treatment period for the full evaluable
population is shown in Table 23. A summary of the total amount of
rescue medication (midazolam, fentanyl) required for sedation and
analgesia while intubated during the treatment period for the full
evaluable population is shown in Table 24. A smaller percentage of
subjects in Group II received rescue midazolam for sedation in
comparison with Group I across all treatment groups in the full
evaluable population, except for in the Dose Level 4 treatment
group, (37.5% vs. 50.0%, 42.9% vs. 66.7%, 25.0% vs. 50.0%, and
25.0% vs. 16.7% in the Dose Level 1, 2, 3, and 4 treatment groups,
respectively, in Group II vs. Group I, respectively). The
differences between age groups in the number of subjects that
received rescue midazolam were not statistically significant in any
of the treatment groups for both the full evaluable and safety
populations. For the safety population overall, there were no
statistically significant differences between dose level groups in
the total amount of rescue medications required for sedation or
analgesia in subjects while intubated.
TABLE-US-00023 TABLE 22 Summary of Percentage of Subjects Who
Received Rescue Midazolam for Sedation During Treatment Period
While Intubated, Stratified by Dose Level and Age Group-Full
Evaluable Population Parameter/ Dose Level 1 Dose Level 2 Dose
Level 3 Dose Level 4 Statistics N = 16 N = 13 N = 14 N = 14 P-value
Group I n (%) 4 (50.0) 4 (66.7) 3 (50.0) 1 (16.7) 0.2446.sup.b
Group II n (%) 3 (37.5) 3 (42.9) 2 (25.0) 2 (25.0) 0.5110.sup.b
Total Age Group n (%) 7 (43.8) 7 (53.8) 5 (35.7) 3 (21.4) --
P-values for 1.0000 0.5921 0.5804 1.0000 -- Differences.sup.a
Overall CMH Test.sup.c -- -- -- -- 0.9997 Raw Mean Scores -- -- --
-- 1 Differ DF Probability -- -- -- -- 0.3174 Abbreviations: CMH =
Cochran-Mantel-Haenszel; midazolam = midazolam .sup.aDifferences
between age Groups I and II within each dose level using Fisher's
exact test. .sup.bP-value of Cochran-Armitage trend test within age
group. .sup.cOverall Cochran-Mantel-Haenszel test with a strata age
group. Note: Group I: Ages .gtoreq.2 through 6 years old; Group II:
Ages .gtoreq.6 through 17 years old. Note: Dose Level 1-Dex LD =
0.25/CD = 0.2 .mu.g/kg/hr Dose Level 2-Dex LD = 0.50/CD = 0.4
.mu.g/kg/hr Dose Level 3-Dex LD = 1.00/CD = 0.7 .mu.g/kg/hr Dose
Level 4-Dex LD = 1.00/CD = 2.00 .mu.g/kg/hr
TABLE-US-00024 TABLE 23 Summary of Weight-Adjusted Total Amount of
Rescue Medication (Midazolam, Fentanyl) Required for Sedation and
Analgesia While Intubated During the Treatment Period- Full
Evaluable Population. Dose Level 1 Dose Level 2 Dose Level 3 Dose
Level 4 Total Amount of DEX DEX DEX DEX Rescue Medication N = 16 N
= 13 N = 14 N = 14 P-value Midazolam (mg/kg).sup.a Mean (SD) 0.067
0.087 0.109 0.045 (0.1024) (0.1646) (0.2229) (0.1053) Median (Min,
Max) 0 0.028 0 0 (0, 0.31) (0, 0.60) (0, 0.82) (0, 0.30) Wilcoxon
0.5766.sup.b Median 0.3751.sup.b Fentanyl (.mu.g/kg).sup.a Mean
(SD) 2.24 191.13 2.84 2.26 (2.114) (668.890) (5.572) (2.601) Median
(Min, Max) 1.91 2.68 1.54 1.75 (0, 8.0) (0, 2417.0) (0, 22.0) (0,
8.0) Wilcoxon 0.6896.sup.b Median 0.3471.sup.b Abbreviations: CD =
continuous dose; DEX = dexmedetomidine; LD = loading dose; MAX =
maximum; midazolam = midazolam; Min = minimum Note: Dose Level
1-Dex LD = 0.25/CD = 0.2 .mu.g/kg/hr Dose Level 2-Dex LD = 0.50/CD
= 0.4 .mu.g/kg/hr Dose Level 3-Dex LD = 1.00/CD = 0.7 .mu.g/kg/hr
Dose Level 4-Dex LD = 1.00/CD = 2.00 .mu.g/kg/hr .sup.aDescriptive
statistics are computed based on total number of subjects whether
or not they used any amount of rescue medication for sedation
during the treatment period while intubated, within each dose
level. .sup.bP-values from Proc NPAR1WAY for specified tests.
TABLE-US-00025 TABLE 24 Summary of Total Amount of Rescue
Medication (Midazolam, Fentanyl) Required for Sedation and
Analgesia While Intubated During the Treatment Period-Full
Evaluable Population. Dose Level 1 Dose Level 2 Dose Level 3 Dose
Level 4 Total Amount of DEX DEX DEX DEX Rescue Medication N = 16 N
= 13 N = 14 N = 14 P-value Midazolam (mg).sup.a Mean (SD) 1.292
1.369 2.141 0.769 (1.8682) (2.3948) (3.9875) (1.8408) Median (Min,
Max) 0 1.000 0 0 (0, 6.00) (0, 8.82) (0, 12.72) (0, 6.00) Wilcoxon
0.5148.sup.b Median 0.3751.sup.b Fentanyl (.mu.g).sup.a Mean (SD)
49.72 3575.97 51.61 35.46 (72.396) (12507.111) (67.885) (39.323)
Median (Min, 36.00 55.00 30.00 33.00 Max) (0, 300.0) (0, 45198.8)
(0, 270.0) (0, 120.0) Wilcoxon 0.5676.sup.b Median 0.6249.sup.b
Abbreviations: CD = continuous dose; DEX = dexmedetomidine; LD =
loading dose; MAX = maximum; midazolam = midazolam; Min = minimum
Note: Dose Level 1-Dex LD = 0.25/CD = 0.2 .mu.g/kg/hr Dose Level
2-Dex LD = 0.50/CD = 0.4 .mu.g/kg/hr Dose Level 3-Dex LD = 1.00/CD
= 0.7 .mu.g/kg/hr Dose Level 4-Dex LD = 1.00/CD = 2.00 .mu.g/kg/hr
.sup.aDescriptive statistics are computed based on total number of
subjects whether or not they used any amount of rescue medication
for sedation during the treatment period while intubated, within
each dose level. .sup.bP-values from Proc NPAR1WAY for specified
tests.
[0223] The time to first rescue medication for sedation and
analgesia in the full evaluable population, as presented in Table
25, demonstrated a trend reflecting longer median times to first
rescue with increasing dose levels with similar time intervals for
Dose Levels 2 and 3 treatment groups (2.2 and 2.5 hours), while the
time to first rescue medication was shorter for the Dose Level 1
treatment group (1.0 hours) and longer for the Dose Level 4
treatment group (7.8 hours). This trend was not statistically
significant (P=0.2391 Log-Rank), as shown in Table 26. A comparable
trend was observed in the safety population, except the effect was
not monotonic. The time to rescue for the Dose Level 2 treatment
group (2.5 hours) was slightly greater than the Dose Level 3
treatment group (2.4 hours).
TABLE-US-00026 TABLE 25 Summary of Time (Hours) to First Dose of
Rescue Medication for Sedation and Analgesia-Full Evaluable
Population Dose Level 1 Dose Level 2 Dose Level 3 Dose Level 4
Overall Parameter Dex Dex Dex Dex P-value.sup.c Median.sup.a 1.0
2.2 2.5 7.8 95% CI.sup.b (0.417, 3.500) (0.600, 3.333) (1.367,
3.867) (1.250).sup.d N (%) Censored 4 (25.0) 2 (15.4) 1 (7.1) 6
(42.9) Log-Rank 0.2391 Wilcoxon 0.2021 Abbreviations: CD =
continuous dose; DEX = dexmedetomidine; LD = loading dose; MAX =
maximum; midazolam = midazolam; Min = minimum Note: Dose Level
1-Dex LD = 0.25/CD = 0.2 .mu.g/kg/hr Dose Level 2-Dex LD = 0.50/CD
= 0.4 .mu.g/kg/hr Dose Level 3-Dex LD = 1.00/CD = 0.7 .mu.g/kg/hr
Dose Level 4-Dex LD = 1.00/CD = 2.00 .mu.g/kg/hr .sup.aDescriptive
statistics are computed based on total number of subjects whether
or not they used any amount of rescue medication for sedation
during the treatment period while intubated, within each dose
level. .sup.bP-values from Proc NPAR1WAY for specified tests.
.sup.cP-value from Log-Rank and Wilcoxon tests for difference
between treatment groups (using PROC LIFETEST with strata dose
level). .sup.dCI lower bound only. No upper bound.
TABLE-US-00027 TABLE 26 Summary of Time (Hours) to First Dose of
Rescue Medication for Sedation and Analgesia-Full Evaluable
Population Dose Level 1 Dose Level 2 Dose Level 3 Dose Level 4
Overall Parameter DEX DEX DEX DEX P-value.sup.c Median.sup.a 1.0
2.5 2.4 7.8 95% CI.sup.b (0.417, 3.500) (0.600, (1.367,
(1.250).sup.d 9.667) 3.417) N (%) Censored 4 (25.0) 3 (21.4) 1
(6.7) 6 (42.9) Log-Rank 0.2617 Wilcoxon 0.2254 Abbreviations: CD =
continuous dose; CI = confidence interval; DEX = dexmedetomidine;
LD = loading dose Note: Summary of time to first dose of rescue
medication for sedation and analgesia done using Kaplan-Meier
Estimates, Log-Rank and Wilcoxon tests. Note: Dose Level 1-Dex LD =
0.25/CD = 0.2 .mu.g/kg/hr Dose Level 2-Dex LD = 0.50/CD = 0.4
.mu.g/kg/hr Dose Level 3-Dex LD = 1.00/CD = 0.7 .mu.g/kg/hr Dose
Level 4-Dex LD = 1.00/CD = 2.00 .mu.g/kg/hr Note: If the subject
received rescue medication, the subject is considered to have the
event. If the subject did not complete the treatment/discontinued,
the subject is censored. .sup.aMedian time to successful extubation
from start of DEX infusion in hours. .sup.b95% CI for median.
.sup.cP-value from Log-Rank and Wilcoxon tests for difference
between treatment groups (using PROC LIFETEST with strata dose
level). .sup.dCI lower bound only. No upper bound.
[0224] In Group I, the mean total doses were 30.9200, 100.1147,
94.0000, and 663.5800 .mu.g for the Dose Level 1, 2, 3, and 4
treatment groups, respectively, with the exception of the Dose
Level 3 treatment group that showed a small decrease, exposure
generally increased as the dose level increased. In Group II, the
mean total doses were 73.1150, 236.9350, 269.2444, and 586.2825
.mu.g for the Dose Level 1, 2, 3, and 4 treatment groups. For all
treatment groups in Group II, exposure increased as the dose level
increased. The total exposure to dexmedetomidine for the safety
population is given in Table 27 below.
TABLE-US-00028 TABLE 27 Total Exposure for Dexmedetomidine-Safety
Population Group I-Dose Level Group II-Dose Level 1 2 3 4 1 2 3 4
Mean Total 30.9 100.1 94.0 663.6 73.1 236.9 269.2 586.3 Dose
(.mu.g)
[0225] Summary statistics for the dexmedetomidine loading doses and
maintenance infusion doses are shown in Table 27A below.
TABLE-US-00029 TABLE 27A Summary Statistics of Dosing-Related Data
Dose-Related 0.25 .mu.g/kg + 0.50 .mu.g/kg + 1.00 .mu.g/kg + 1.00
.mu.g/kg + Variable 0.20 .mu.g/kg/h 0.40 .mu.g/kg/h 0.70 .mu.g/kg/h
2.00 .mu.g/kg/h Loading dose (ng) Mean (SD) 7021.333 12237.143
28765.333 36904.286 (6098.953) (7955.193) (21368.168) (35112.824)
Median 4400.000 9800.000 23400.000 20900.000 Min, Max 2800.00,
5200.00, 12000.00, 12000.00, 24800.00 35480.00 98000.00 140000.00 n
15 14 15 14 Maintenance Mean (SD) 42797.333 108335.571 170381.333
473520.000 infusion dose (ng) (33346.443) (86027.962) (151015.142)
(196870.668) Median 26520.000 104400.000 117600.000 462200.000 Min,
Max 12000.00, 22760.00, 58800.00, 153080.00, 125200.00 360920.00
595600.00 828800.00 n 15 14 15 14 Total dose (ng) Mean (SD)
49818.667 120572.714 199146.667 510424.286 (38564.475) (92121.808)
(158726.350) (202156.184) Median 32000.000 117000.000 141600.000
474800.000 Min, Max 14800.00, 33200.00, 70800.00, 165880.00,
150000.00 396400.00 635200.00 892360.00 n 15 14 15 14 Loading
infusion Mean (SD) 0.167 (0.000) 0.167 (0.000) 0.167 (0.000) 0.167
(0.000) duration (h) Median 0.167 0.167 0.167 0.167 Min, Max 0.17,
0.17 0.17, 0.17 0.17, 0.17 0.17, 0.17 n 15 14 15 14 Maintenance
Mean (SD) 7.919 (3.855) 11.514 8.792 (5.371) 10.196 infusion Median
6.000 (6.771) 7.000 (4.837) duration (h) Min, Max 487, 15.83 7.000
2.50, 20.25 7.075 n 15 2.25, 20.82 15 6.00, 17.67 14 14 Time
between Mean (SD) 10.533 10.214 10.400 10.357 start of doses Median
(1.302) (0.579) (1.298) (1.336) (min) Min, Max 10.000 10.000 10.000
10.000 n 10.00, 15.00 10.00, 12.00 10.000, 15.00 10.00, 15.00 15 14
15 14 Time from end of Mean (SD) 0.533 (1.302) 0.214 (0.579) 0.400
(1.298) 0.357 (1.336) 1.sup.st to beginning of Median 0.000 0.000
0.000 0.000 2.sup.nd infusion (min) Min, Max 0.00, 5.00 0.00, 2.00
0.00, 5.00 0.00, 5.00 n 15 14 15 14
[0226] The mean dexmedetomidine concentration profiles (over time)
for the Dose Levels 1 and 2 were similar and remained generally the
same over time as illustrated in FIG. 1. For the Dose Level 3
treatment group, the mean plasma dexmedetomidine concentration
showed a sharp increase at the end of the loading dose compared to
other dose levels. The sharp increase was the result an excessively
high plasma dexmedetomidine concentration at the end of the loading
dose in a subject (Subject 123009) in the Dose Level 3 treatment
group. Subject 123009 had a mean area under the concentration-time
curve from time zero to the time of the last measurable
concentration (AUC.sub.0-t)=116910.2 .mu.g/mL/hr and area under the
concentration-time curve from time zero to the time infinity
(AUC.sub.0-.infin.)=117264.1 .mu.g/mL/hr, and C.sub.max=28804.30
.mu.g/mL). Mean plasma concentrations of dexmedetomidine tended to
increase with increasing dose levels. The highest mean plasma
concentrations were observed in the Dose Level 4 treatment group.
The mean concentration at the end of the maintenance infusion, AUC,
C.sub.ss, and C.sub.max values increased with increasing dose.
[0227] The mean half-life values for the Dose Level 1, 2, 3, and 4
treatment groups (combined across age groups) were 1.546, 1.743,
2.045, and 2.145 hours, respectively. The apparent increase in
half-life with increasing dose levels is due to many of the
concentrations used to calculate the half-life for the lower dose
levels being below the limit of quantitation.
[0228] Statistically significant differences were observed between
Groups I and II within each dose level for the pharmacokinetic
parameters of V.sub.d (p=0.0046), weight adjusted V.sub.d
(p=0.0040), and CL (p=0.0078), and weight adjusted CL (p=0.0094),
as shown in Table 28.
TABLE-US-00030 TABLE 28 Summary of Statistically Significant
Differences Between Group I and Group II Subjects Within Each Dose
Level for Pharmacokinetic Parameters-Full Evaluable Population
Geometric Means.sup.a,b Dose Level 1 Dose Level 2 Dose Level 3 Dose
Level 4 Parameter/ DEX DEX DEX DEX Statistics N = 16 N = 14 N = 15
N = 14 P-Value Group I V.sub.d 36.91 31.77 46.64 36.29 CL 16.24
12.73 16.59 11.93 Group II V.sub.d 51.70 61.17 46.58 72.82 CL 24.69
24.76 16.44 25.36 Differences.sup.c V.sub.d -0.337 -0.655 0.001
-0.696 0.0046 (-1.399, (-1.096, (-0.626, (-1.212, 0.725) -0.215)
0.628) -0.181) CL -0.419 -0.665 0.009 -0.754 0.0078 (-1.669,
(-1.068, (-0.663, (-1.389, 0.831) -0.262) 0.680) -0.119)
Abbreviations: CD = continuous dose; CL = plasma clearance; DEX =
dexmedetomidine; LD = loading dose; PK = pharmacokinetics; V.sub.d
= volume of distribution Note: Dose Level 1-Dex LD = 0.25/CD = 0.2
.mu.g/kg/hr Dose Level 2-Dex LD = 0.50/CD = 0.4 .mu.g/kg/hr Dose
Level 3-Dex LD = 1.00/CD = 0.7 .mu.g/kg/hr Dose Level 4-Dex LD =
1.00/CD = 2.00 .mu.g/kg/hr
[0229] Statistically significant differences (p<0.05) were
observed in PK parameters by dose level for AUC.sub.0-t, C.sub.max,
t.sub.1/2, C.sub.ss and .lamda.z and by age for Css (p=0.0167),
C.sub.max (p=0.0053), V.sub.d (p=0.0089) and CL (p=0.0125), and
weight adjusted V.sub.d (p=0.0055) and CL (p=0.0190).
[0230] Pharmacokinetic parameters of dexmedetomidine in the full
evaluable population were summarized using descriptive statistics
and are presented in Table 29. Similar results were obtained in
subjects that underwent cardiopulmonary bypass surgery.
TABLE-US-00031 TABLE 29 Summary of Pharmacokinetic Parameters-Full
Evaluable Population Parameter/ Dose Level 1 Dose Level 2 Dose
Level 3 Dose Level 4 Statistics DEX DEX DEX DEX Primary
Pharmacokinetic Parameters AUC.sub.0-t [(.mu.g/mL)hr] 14 13 14 14
(N) Mean (SD) 2681.332 6460.576 16992.540 28531.864 (2353.3418)
(3766.4657) (29927.3911) (17496.3985) Median (Min, Max) 1540.417
5247.638 5606.310 25411.857 (779.88, 9266.09) (1900.23, (4257.50,
(10027.42, 12194.00) 116910.2) 68850.45) % CV 87.77 58.30 176.12
61.32 AUC.sub.0-.infin. [(.mu.g/mL)hr] 12 13 14 14 (N) Mean (SD)
3153.518 6673.163 17300.539 28970.541 (3343.3451) (3781.2183)
(29935.7647) (17936.8970) Median (Min, Max) 1583.539 5521.515
6078.304 25675.767 (923.23, (2023.22, (4568.71, (10093.96,
12681.98) 12413.04) 117264.1) 70764.26) % CV 106.02 56.66 173.03
61.91 C.sub.max (.mu.g/mL)(N) 14 13 14 14 Mean (SD) 480.437 847.691
3385.569 3090.939 (625.9946) (633.7352) (7384.0699) (1625.5241)
Median (Min, Max) 266.465 581.040 966.235 2686.210 (169.58,
(399.60, (534.11, (1540.85, 2558.19) 2456.03) 28804.30) 6810.13) %
CV 130.30 74.76 218.10 52.59 T.sub.max (hours)(N) 14 13 14 14 Mean
(SD) 7.307 (5.7937) 8.805 (9.5105) 2.174 (2.7535) 6.815 (5.9039)
Median (Min, Max) 6.042 5.683 0.167 5.417 (0.08, 16.17) (0.12,
20.93) (0.08, 6.33) (0.13, 17.60) % CV 79.29 108.01 126.66 86.63
t.sub.1/2 (hours)(N) 12 13 14 14 Mean (SD) 1.546 (0.3401) 1.743
(0.3018) 2.045 (0.6582) 2.145 (0.6763) Median (Min, Max) 1.556
(1.03, 2.28) 1.687 (1.27, 1.795 (1.24, 2.125 (0.98, 2.45) 3.33)
3.33) % CV 22.00 17.31 32.18 31.53 .lamda..sub.z (1/hour)(N) 12 13
14 14 Mean (SD) 0.469 (0.1062) 0.408 (0.0672) 0.369 (0.1037) 0.360
(0.1350) Median (Min, Max) 0.446 (0.30, 0.67) 0.411 (0.28, 0.386
(0.21, 0.326 (0.21, 0.54) 0.56) 0.71) % CV 22.64 16.46 28.13 37.56
C.sub.ss (.mu.g/mL)(N) 12 13 14 14 Mean (SD) 402.026 539.848
1347.284 2827.144 (535.1718) (166.7423) (1308.0988) (1169.4226)
Median (Min, Max) 197.991 513.902 947.907 2665.409 (149.71,
(282.31, (637.50, (1602.66, 2056.54) 868.84) 5743.55) 5429.48) % CV
133.12 30.89 97.09 41.36 V.sub.d (L)(N) 12 13 14 14 Mean (SD)
61.982 50.632 52.328 62.186 (66.0605) (26.2671) (25.5848) (34.7628)
Median (Min, Max) 42.960 40.657 51.303 57.802 (13.76, 238.30)
(23.67, 95.26) (17.22, 100.71) (23.17, 138.40) % CV 106.58 51.88
48.89 55.90 V.sub.ss (L)(N) 12 13 14 14 Mean (SD) 56.808 (44.5127)
-8.363 32.789 43.652 (156.5060) (22.5478) (30.6577) Median (Min,
Max) 40.264 30.633 30.400 33.114 (4.25, 144.02) (-522.63, (3.38,
88.22) (12.09, 122.08) 83.53) % CV 78.36 -1871.30 68.77 70.23
Weight-adjusted V.sub.d 12 13 14 14 (L/kg)(N) Mean (SD) 2.167
(0.8564) 2.315 (0.8392) 2.441 (1.3576) 2.484 (0.9016) Median (Min,
Max) 2.429 2.486 2.187 2.152 (0.28, 3.38) (1.31, 4.04) (0.57, 5.83)
(1.19, 4.41) % CV 39.53 36.24 55.62 36.30 CL (L/hr)(N) 12 13 14 14
Mean (SD) 32.208 (40.3982) 20.268 18.565 22.199 (10.3508) (8.6995)
(14.1623) Median (Min, Max) 19.531 16.040 16.170 16.890 (5.37,
147.15) (10.43, 39.50) (3.76, 39.47) (7.42, 49.96) % CV 125.43
51.07 46.86 63.80 Weight-adjusted CL 12 13 14 14 (L/hr/kg)(N) Mean
(SD) 1.039 (0.4826) 0.919 (0.3021) 0.842 (0.3339) 0.849 (0.3010)
Median (Min, Max) 1.196 0.884 0.881 0.803 (0.11, 1.65) (0.55, 1.66)
(0.13, 1.27) (0.35, 1.28) % CV 46.46 32.88 39.65 35.44
Abbreviations: .lamda..sub.z = terminal elimination rate constant;
AUC.sub.0-.infin. = area under the concentration-time curve from
time zero to the time infinity; AUC.sub.0-t = area under the
concentration-time curve from time zero to the time of the last
measurable concentration; CD = continuous dose; CL = plasma
clearance; C.sub.max = observed peak plasma concentration; C.sub.ss
= steady state concentration; CV = coefficient of variation; DEX =
dexmedetomidine; LD = loading dose; Max = maximum; Min = minimum;
T.sub.max = time of maximum concentration; t.sub.1/2 = terminal
elimination half-life; V.sub.d = volume of distribution; V.sub.ss =
volume of steady state distribution. Note: Dose Level 1-Dex LD =
0.25/CD = 0.2 .mu.g/kg/hr Dose Level 2-Dex LD = 0.50/CD = 0.4
.mu.g/kg/hr Dose Level 3-Dex LD = 1.00/CD = 0.7 .mu.g/kg/hr Dose
Level 4-Dex LD = 1.00/CD = 2.00 .mu.g/kg/hr
[0231] Plasma clearance over age, weight and weight-adjusted
clearance over age are presented in FIGS. 2-4, respectively.
Weight-adjusted clearance for 2-year-old patients was approximately
1 L/hr/kg and decreased with age until values were approximately
that observed in adults (0.6 L/kg/hr).
[0232] The pharmacokinetic analysis demonstrated dose
proportionality and a linear relationship among the Dose Level 1,
2, 3, and 4 treatment groups and AUC and C.sub.max. The predicted
mean curves for AUC.sub.0-.infin., AUC.sub.0-t, C.sub.max, and
C.sub.ss generated using the power fit model are presented in FIGS.
6-9, respectively. As dose increased, AUC and C.sub.max increased
in proportion (FIG. 1 and Table 29).
[0233] AUC.sub.0-.infin. and AUC.sub.0-t of dexmedetomidine
displayed positive linearity among the Dose Level 1, 2, 3, and 4
treatment groups. The C.sub.max of dexmedetomidine displayed
positive linearity for the Dose Level 1, 2, and 3 treatment groups
and showed a slight decrease in the Dose Level 4 treatment group.
The apparent t.sub.1/2 of dexmedetomidine was 1.546, 1.743, 2.045,
and 2.145 hours for the Dose Level 1, 2, 3, and 4 treatment groups,
respectively. Statistically significant differences were observed
between Groups I and II only for the pharmacokinetic parameters of
V.sub.d (p=0.0046), weight-adjusted V.sub.d (p=0.0040), CL
(p=0.0078), and weight-adjusted CL (p=0.0094). Weight-adjusted
clearance decreased with age until values were approximately that
observed in adults. No noticeable increases or decreases in V.sub.d
or weight-adjusted V.sub.d for increasing age or weight were
observed.
[0234] Statistically significant differences were observed for the
pharmacokinetic parameters for the main effect of dose level for
AUC.sub.0-t, AUC.sub.0-.infin., C.sub.ss, C.sub.max, .lamda.z, and
t.sub.1/2 and the main effect age for C.sub.ss, C.sub.max, V.sub.d,
weight-adjusted V.sub.d, CL, and weight-adjusted CL using a two-way
analysis of variance (ANOVA). However, there were no statistically
significant dose level by age group interactions observed for any
of the pharmacokinetic parameters. A summary of key pharmacokinetic
parameters for the full evaluable population is given in Table 30
below.
TABLE-US-00032 TABLE 30 Summary of Key Pharmacokinetic Parameters
for the Full Evaluable Population Dose Level 1 Dose Level 2 Dose
Level 3 Dose Level 4 Parameter DEX (N = 14) DEX (N = 13) DEX (N =
14) DEX (N = 14) P-value.sup.a AUC.sub.0-t 2681.3 6460.6 16992.5
28531.9 <0.0001 [(pg/mL)hr] (2353.34) (3766.47) (29927.39)
(17496.40) C.sub.max (pg/mL) 480.4 847.7 3385.6 3090.9 <0.0001
(625.99) (633.74) (7384.07) (1625.52) t.sub.1/2 (hr) 1.5 (0.34) 1.7
(0.30) 2.0 (0.66) 2.1 (0.68) 0.0381 AUC.sub.0-.infin. 3153.5 6673.2
17300.5 28970.5 <0.0001 [(pg/mL)hr] (3343.35) (3781.22)
(29935.76) (17936.90) C.sub.ss(pg/mL) 402.0 539.8 1347.3 2827.1
<0.0001 (535.17) (166.74) (1308.10) (1169.42) .lamda..sub.z
(1/hr) 0.5 (0.11) 0.4 (0.07) 0.4 (0.10) 0.4 (0.14) 0.0381 V.sub.d
(L) 62.0 (66.06) 50.6 (26.27) 52.3 (25.58) 62.2 (34.76) 0.8210
Weight-adjusted 2.2 (0.86) 2.3 (0.84) 2.4 (1.36) 2.5 (0.90) 0.6394
V.sub.d (L/kg) CL (L/hr) 32.2 (40.40) 20.3(10.35) 18.6 (8.70) 22.2
(14.16) 0.8439 Weight-adjusted 1.0 (0.48) 0.9 (0.30) 0.8 (0.33) 0.8
(0.30) 0.8769 CL (L/hr/kg) Abbreviations: .lamda..sub.z = terminal
elimination rate constant; AUC.sub.0-.infin. = area under the
concentration-time curve from time zero to the time infinity;
AUC.sub.0-t = area under the concentration-time curve from time
zero to the time of the last measurable concentration; CL = plasma
clearance; C.sub.max = observed peak plasma concentration; C.sub.ss
= steady state concentration; DEX = dexmedetomidine; LD = loading
dose; t.sub.1/2 = terminal elimination half-life; V.sub.d = volume
of distribution. .sup.aResults of two-way analysis of variance
(ANOVA) to evaluate the effect of dose level on age group for PK
parameters. Note: Dose Level 1-Dex LD = 0.25/CD = 0.2 .mu.g/kg/hr
Dose Level 2-Dex LD = 0.50/CD = 0.4 .mu.g/kg/hr Dose Level 3-Dex LD
= 1.00/CD = 0.7 .mu.g/kg/hr Dose Level 4-Dex LD = 1.00/CD = 2.00
.mu.g/kg/hr
[0235] The pharmacodynamic parameters measured in Groups I and II
were level of sedation, number of subjects who received rescue
medication (midazolam and fentanyl), amount of rescue medication
required for sedation and analgesia, vital signs (I-IR, SBP, DBP,
MAP, RR, and SpO.sub.2), time to successful extubation, and
comparison of RSS.sub.avg with AUC.sub.0-.infin. and C.sub.ss. The
RSS scores (e.g., RSS.sub.5 and RSS.sub.avg) were generally similar
across dose levels and between Groups I and II, although the
RSS.sub.5 and RSS.sub.avg scores in the Dose Level 4 treatment
group of Group II were slightly higher compared to other treatment
groups in Groups I and II. For subjects that received
dexmedetomidine alone, the RSS.sub.5 and RSS.sub.avg scores were
higher across treatment groups in Group II compared to Group I. For
subjects that received dexmedetomidine with the co-administration
of midazolam or fentanyl, the RSS5 and RSS.sub.avg scores were
generally similar between subjects in all treatment groups and
across age groups with the exception of subjects in the Dose Level
4 treatment group in Group II. The RSS5 and RSSavg scores in the
Dose Level 4 treatment group of Group II (RSS5=4.5 and RSSavg=4.5)
were slightly higher compared to other treatment groups (RSS5
scores range=2.5 to 3.7) in Groups I and II in the full evaluable
population. Similar results were observed in the safety
population.
[0236] As described above, one subject in the Dose Level 3
treatment group had extremely high plasma dexmedetomidine
concentration at the end of the loading infusion. The plasma
concentration data from this subject skewed the calculated AUC and
C.sub.ss results. FIGS. 10 and 11 show the relationship between
RSS.sub.avg and AUC and C.sub.ss, respectively. With this subject,
who had a mean AUC value of 117264.1 .mu.g hr/mL and C.sub.ss of
5743.55 .mu.g/mL, excluded from the analyses, there was an increase
in RSS.sub.avg with increasing AUC and C.sub.ss.
[0237] A smaller percentage of subjects in Group II received rescue
midazolam for sedation compared to Group I across all treatment
groups. In comparison to the other three dose level treatment
groups, fewer subjects in the Dose Level 4 treatment group required
rescue medication. There was also an increase in the time to the
administration of the first dose of rescue medication in this
treatment group in the Dose Level 4 treatment group, because of the
increased level of sedation in this treatment group. The
differences between these age groups in the number of subjects that
received rescue midazolam were not statistically significant in any
age group at any dose level. The amount of rescue medication
required for sedation and analgesia during the treatment period was
similar across all dose levels. No statistically significant
differences were observed in the amount of midazolam or fentanyl
used as rescue medication for sedation or analgesia between
treatment groups in the safety population. In general, the majority
of subjects treated across age groups and dose levels required
co-administration of midazolam or fentanyl with dexmedetomidine
with the exception of Group II Dose Level 4 treatment group, in
which 3 of 8 subjects received co-administration of midazolam or
fentanyl.
[0238] In the full evaluable population, the median times to
extubation increased with dose. The time intervals for the Dose
Levels 1, 2, and 3 treatment groups were similar (0.6-1.7 hours),
while the time to extubation Dose Level 4 treatment group was
longer (6.8 hours). The effect was not statistically significant
(p=0.3041). Similar results were seen for the safety population.
The summary of time to successful extubation for the full evaluable
population is given in Table 31 below.
TABLE-US-00033 TABLE 31 Summary of Time to Successful
Extubation-Full Evaluable Population Parameter Dose Level 1 Dose
Level 2 Dose Level 3 Dose Level 4 Overall P-value.sup.c
Median.sup.a 0.6 0.8 1.7 6.8 -- 95% CI.sup.b (0.433, 3.000) (0.533,
2.417) (0.633, 4.417) (0.667, 7.333) -- N (%) Censored 3 (18.8) 0 2
(14.3) 2 (14.3) -- Log-Rank -- -- -- -- 0.3041 Wilcoxon -- -- -- --
0.1555 Abbreviations: CD = continuous dose; CI = confidence
interval; DEX = dexmedetomidine; LD = loading dose; Note: Summary
of time to successful extubation was done using Kaplan-Meier
Estimates, Log-Rank and Wilcoxon tests. Note: Dose Level 1-Dex LD =
0.25/CD = 0.2 .mu.g/kg/hr Dose Level 2-Dex LD = 0.50/CD = 0.4
.mu.g/kg/hr Dose Level 3-Dex LD = 1.00/CD = 0.7 .mu.g/kg/hr Dose
Level 4-Dex LD = 1.00/CD = 2.00 .mu.g/kg/hr Note: If extubation was
successful, the subject is considered to have the event. If the
subject did not complete the treatment/discontinued, the subject is
censored. .sup.aMedian time to successful extubation from start of
DEX infusion in hours. .sup.b95% CI for median. .sup.cP-value from
Log-Rank and Wilcoxon tests for difference between treatment groups
(using PROC LIFETEST with strata dose level).
[0239] No clinically meaningful trends in the mean change from
baseline in HR, SBP, DBP, MAP, RR, or SpO.sub.2 were observed in
Group I and Group II subjects during infusion and post-infusion.
Similarly, no clinically meaningful trends were seen in the mean
change from baseline in HR, SBP, DBP, or MAP in subjects stratified
by whether or not they underwent cardiopulmonary bypass
surgery.
[0240] Treatment-related adverse events occurred primarily during
the loading dose and only in Dose Levels 3 and 4. The most
frequently reported non drug-related treatment emergent adverse
effects in both age groups were pyrexia, vomiting, hypokalaemia,
and hypertension. In Group I (26 subjects), the treatment-related
TEAEs were bradycardia (2 subjects), hypotension (1 subject),
sedation (2 subjects), hypertension (1 subject). In Group II (33
subjects), the treatment-related TEAEs were bradycardia (1
subject), sedation (1 subject), hypertension (5 subjects), and
chills (1 subject).
[0241] The majority of these adverse effects were considered not
related to the study drug and mild or moderate in intensity.
Numerical differences were observed in several hematology,
chemistry, and urinalysis parameters with increasing or decreasing
trends among treatment groups in lymphocytes, neutrophils,
platelets, ALP, AST, and bilirubin. Although numerical changes
occurred, no clinically meaningful trends in the mean change from
baseline in HR, SBP, DBP, MAP, RR, and SpO.sub.2 between treatment
groups were observed among treatment groups. Respiratory rate was
not affected. Similar results were obtained in subjects stratified
by whether or not they underwent cardiopulmonary bypass
surgery.
[0242] The change from Baseline in SBP tended to increase from Dose
Level 1 to 4 for subjects who underwent CPB surgery. These
differences were not clinically significant. No similar observation
was noted in subjects who did not undergo CPB surgery.
[0243] Except for the slightly higher SBP observed in subjects who
underwent CPB surgery in the Dose Level 4 treatment group, the 4
dose levels of dexmedetomidine studied were generally well
tolerated in this study and there were no clinically meaningful
differences observed between dose levels in the safety profile of
dexmedetomidine.
[0244] There were no clinically meaningful changes from baseline in
the clinical laboratory test results observed across treatment
groups during infusion and post-infusion. Hematology results that
showed large numerical changes from Baseline included lymphocytes,
neutrophils, and platelets. Chemistry results that showed large
numerical changes from Baseline included ALP, AST, and
bilirubin.
[0245] The majority of ECG findings reported were normal or
abnormal but not clinically significant. The majority of subjects
had unremarkable physical examination findings in all body system
categories except the cardiopulmonary body system. No clinically
meaningful changes in vital signs, laboratory test results or ECGs
were observed across treatment groups during infusion and
post-infusion. In general, dexmedetomidine was well tolerated in
intubated and mechanically ventilated pediatric patients in this
study.
[0246] No deaths were reported. One subjected experienced
convulsion that was considered mild and not related to study drug.
Drug-related treatment-emergent adverse effects (TEAE5) were
reported at Dose Levels 3 and 4, as shown in Table 32.
TABLE-US-00034 TABLE 32 Drug-Related Treatment-Emergent Events by
Preferred Term-Safety Population Group I DEX Dose DEX Dose DEX Dose
DEX Dose Level 1 Level 2 Level 3 Level 4 (N = 8) (N = 6) (N = 6) (N
= 6) Subjects with at 0 0 1 (16.7) 4 (66.7) least 1 Drug- Related
TEAE, n (%) Number of Drug-related 0 0 2 4 TEAE Bradycardia 0 0 1
(16.7) 1 (16.7) Sedation 0 0 0 2 (33.3) Hypertension 0 0 1 (16.7) 0
Hypotension 0 0 0 1 (16.7) Group II DEX Dose DEX Dose DEX Dose DEX
Dose Level 1 Level 2 Level 3 Level 4 (N = 8) (N = 8) (N = 9) (N =
8) Subjects with at 0 0 2 (22.2) 4 (50.0) least 1 Drug- Related
TEAE, n (%) Number of Drug-related 0 0 3 4 TEAE Bradycardia 0 0 1
(11.1) 0 Chills 0 0 1 (11.1) 0 Sedation 0 0 0 1 (12.5) Hypertension
0 0 1 (11.1) 3 (37.5) Abbreviations: DEX = dexmedetomidine; TEAE =
Treatment Emergent Adverse Events. Investigator adverse event (AE)
terms were coded to preferred terms using Medical Dictionary for
Regulatory Activities (MedDRA) dictionary version 11.0).
Percentages are based on the number of subjects in each treatment
group by age group. Subjects are counted once within each system
organ class or for each preferred term and may have had more than 1
TEAE. Related is any event that was assessed as either unknown
relation, unlikely, possibly, probably/likely or certainly related
to study medication. If a subject had more than one occurrence of
the same TEAE, the highest relationship to study drug was
summarized. Note: Dose Level 1-Dex LD = 0.25/CD = 0.2 .mu.g/kg/hr
Dose Level 2-Dex LD = 0.50/CD = 0.4 .mu.g/kg/hr Dose Level 3-Dex LD
= 1.00/CD = 0.7 .mu.g/kg/hr Dose Level 4-Dex LD = 1.00/CD = 2.00
.mu.g/kg/hr
Example 4: Effects of Dexmedetomidine in the Prenatal Cynomolgus
Monkey Brain
[0247] The study was conducted to determine the potential
neuroapoptotic effect of dexmedetomidine in prenatal Cynomolgus
monkey brains by administering dexmedetomidine to pregnant monkeys.
The overall objective of this study was to demonstrate that
dexmedetomidine, an anesthetic with a different mechanism of action
than that of isoflurane or ketamine, does not cause neuroapoptosis
in prenatal cynomolgus monkey brains. The purpose of the
immunohistochemistry analysis of this study was to assess and
characterize the regions of interest histopathologically, and to
characterize and compare test article-induced apoptosis between
groups.
[0248] The monkey model used is that described in Slikker et al.
Tox. Sci. 2007; 98(1), 145-58, which is hereby incorporated by
reference in its entirety. The fetus was removed from the pregnant
female at 120.+-.7 days gestation after a 12 hour intravenous
fusion of dexmedetomidine followed by a 6 hour post-infusion
observation period. The fetal brain was collected by cesarean
section. The treatment groups are shown in Table 33 below.
TABLE-US-00035 TABLE 33 Experimental design Groups (n = 5)
Treatment Route of administration Dose 1 Cage control Not
applicable Not applicable 2 Ketamine Intramuscular + 20 mg/kg im +
Intravenous infusion 20-50 mg/kg/hr 3 Dexmedetomidine Intravenous
injection + 3 ug/kg .times. 10 min + Intravenous infusion 3
ug/kg/hr 4 Dexmedetomidine Intravenous injection + 30 .mu.g/kg
.times. 10 min + Intravenous infusion 30 .mu.g/kg/hr
[0249] Following treatment, animals were sacrificed, and brain
tissues were fixed in 10% neutral buffered formalin via perfusion.
A vibratome microtome was used to generate serial unstained brain
sections at 50- to 70-.mu.m thicknesses, yielding approximately 800
sections per brain. Fixed brain tissue was processed from 20
animals. For each animal, approximately 25 intervaled sections per
brain were stained with the following stains: hematoxylin and eosin
(H&E), silver stain, terminal deoxynucleotidyl transferase dUTP
nick end labeling (TUNEL), and activated Caspase 3 (AC3). The
sections were evaluated by an American College of Veterinary
Pathologists (ACVP) board-certified pathologist, including the use
of image analysis to assess and compare the incidence and
distribution of apoptotic cells in the TUNEL- and AC3-stained
sections.
[0250] Fixed tissues were gross trimmed, processed, oriented and
embedded in paraffin, and sectioned at approximately 35- to
40-.mu.m thicknesses. Each brain was carefully oriented and gross
trimmed into each block to assure correlative symmetry between
animals. Six consecutive blocks were prepared for each brain and
spanned the entire frontal cortex. Approximately 100 unstained
sections were microtomed for each block for a total of about 600
sections per animal. For each block, section level 1, 25, 50 and
100 were selected for staining. Assessments were conducted to
assure that the section levels selected and examine correlated well
between animals. Assessments were also conducted to confirm that
the ketamine-induced lesions were confined to the 1 and 2 layers of
the frontal cortex and that the lesion was distributed consistently
in this region in all animals as reported by Slikker. Approximately
25 serial sections from each brain were stained by one of the
following techniques. H&E stain was used to define general
histology and morphology. Silver staining was used to visualize
neurodegeneration. TUNEL is a method for detecting DNA
fragmentation by labeling the terminal end of nucleic acids. AC3,
detected by IHC antibody staining, is a marker for apoptotic cells.
Following staining, tissues were evaluated by light microscopy by a
board-certified veterinary pathologist. All procedures were
consistent with CBI SOPs; details are maintained in the study
records.
[0251] The modified silver method was employed on brain sections.
See Xuemin Ye et al. 2001, Brain Research Protocols 8, 104-112,
which is hereby incorporated by reference in its entirety. Briefly,
the sections were de-waxed in xylene and rehydrated in alcohol. The
following steps were employed: dehydrate with 50, 75, and 97%
1-propanol for at least 5 minutes each; esterified in sulfuric
acid/1-propanol at 56.degree. C. for 16 hours; rehydrate with 50
and 25% 1-propanol followed by two changes of distilled water, 5
minutes each; wash with 1% acetic acid for exactly 10 minutes;
place in the developing solution until the sections turn brown in
color (ca. 6-8 minutes); terminate development by washing with 1%
acetic acid (30 minutes); and dehydrate, clear and cover slip.
[0252] For activated caspase 3 staining, tissues were
deparaffinized, hydrated, and subjected to heated citrate buffer
antigen retrieval. Tissues were stained on a DAKO Autostainer.
Tissues were reacted with peroxidase and two protein blocks.
Following rinsing in buffer, tissues were then incubated at room
temperature for 60 minutes with 1:275 dilution of AC-3 (Abcam)
followed by incubation for 30 minutes with Envision goat
anti-rabbit secondary antibody (Envision). The immunoreaction was
visualized with DAB and counterstaining with hematoxylin. Both
positive (human tonsil) and negative tissues (human uterus), plus
tissues stained with irrelevant antibody and with saline were
included.
[0253] For TUNEL staining, tissues were deparaffinized, hydrated,
and subjected to heated citrate buffer antigen retrieval. Tissues
were stained either on a DAKO Autostainer or were hand stained
using the Trevigen TACS 2TdT-DAB In Situ Apoptosis Detection Kit.
Both positive (human tonsil) and negative tissues (human uterus),
plus tissues stained with irrelevant antibody and with saline were
included.
[0254] Extensive areas of the frontal cortex and multiple levels
through the frontal cortex were examined with special emphasis on
the lamina. The remainder of the brain tissue on the slides was
also examined for any other lesions. Representative
photomicrographs were taken. H&E-silver-stained, TUNEL and AC3
sections were qualitatively examined by the Study Pathologist, a
veterinary pathologist certified by the American College of
Veterinary Pathologists (ACVP). The incidence and severity of the
lesions (presence of apoptosis and cell injury) were scored using
the accepted industry scoring system: 0=normal, 1=minimal, 2=mild,
3=moderate; and 4=severe.
[0255] Severity scoring of the treatment-related findings is
presented in Table 34. There were abundant neuroapoptotic lesions
of the cortex present in the ketamine-treated group, while there
were minimal changes seen in the dexmedetomidine-treated groups,
particularly in the low(therapeutic)-dose group.
TABLE-US-00036 TABLE 34 Summary of severity scoring of
neuroapoptotic lesions Fetal Brains Activated Group Treatment Dose
Examined HE Silver caspase 3 TUNEL 1 Cage control Untreated 5 0.0
.+-. 0.0 0.6 .+-. 0.6 0.8 .+-. 0.6 0.0 .+-. 0.0 2 Ketamine 20 mg/kg
5 1.9 .+-. 1.2 2.0 .+-. 0.8 3.5 .+-. 0.7 2.9 .+-. 1.1 im + 20-50
mg/kg/hr 3 Dexmedetomidine 3 ug/kg .times. 5 0.1 .+-. 0.3 1.0 .+-.
1.1 1.4 .+-. 0.6 0.1 .+-. 0.2 10 min + 3 ug/kg/hr 4 Dexmedetomidine
30 .mu.g/kg + 5 0.0 .+-. 0.1 0.4 .+-. 0.6 1.8 .+-. 0.9 0.8 .+-. 0.9
30 .mu.g/ kg/hr
[0256] Severity scoring of the treatment-related findings is
presented in Table 34.
[0257] Representative photomicrographs of TUNEL staining of frontal
cortexes are shown in FIG. 12. Representative photomicrographs of
AC3 staining of frontal cortexes are shown in FIGS. 13 and 14.
Representative photomicrographs of silver staining of frontal
cortexes are shown in FIG. 15.
[0258] In Group 1, untreated brains, examination of HE, Silver,
TUNEL and AC3 stained sections from the frontal cortex demonstrated
no or rare, sporadically damaged and apoptotic cells in the layers
of frontal cortex. There was some low intensity positive nuclear
AC3 staining particularly in the white matter, which is indicative
of normal fetal development. There were also a few TUNEL positive
cells in other areas of the brain, but there were no differences
between control and treated brains.
[0259] In Group 2, the ketamine-treated group, examination of HE,
Silver, TUNEL and AC3 sections from the frontal cortex demonstrated
a moderate to large number of damaged and apoptotic cells that was
dramatically increased in comparison to untreated and
dexmedetomidine-treated brains. AC3 marks neurons that are
undergoing apoptotic degeneration after exposure to apoptogenic
drugs including isoflurane. AC3 stained cells are also the same
cells that are stained by silver stains that mark cells that are
dead or dying. AC3 also reveals if cells are in an early or
advanced state of degeneration and what type of cell is undergoing
degeneration (Bambrink, 2010). In early states, there is abundant
AC3 protein in the cell body and processes, therefore the
degenerate cell can be visualized microscopically. Following cell
death, the cell body becomes condensed and rounded up.
[0260] Both of these morphologies were abundantly visible in
ketamine-treated brains but were minimally visible in the
dexmedetomidine-treated brains. The lesions seen in this study were
characterized by a moderate multifocal amount of necrolytic debris,
degenerate axons and cell bodies and apoptotic nuclei in the layers
of the I-VI lamina of the cortex with the most intense staining in
layer I and II. The cell types affected included cells with the
morphology and arborization patterns of .gamma.-aminobutyric
acid-ergic inhibitory interneurons (layer II) and small pyramidal
neurons (likely glutamateric, thought to project to the visual
neurons in the contralateral hemisphere) (Bambrink, 2010). Affected
large multipolar neurons (commonly in layers V and VI), large and
small pyramidal neurons (layers IV and V) and interneurons in layer
II were also evident.
[0261] These observations are very similar to those described by
Bambrink, 2010 with isoflurane-treated rhesus monkeys. There were
also sporadic AC-3 positive cells scattered in the deeper white
matter in all groups, including control.
[0262] In Group 3, the low dose dexmedetomidine group, examination
of HE, Silver, TUNEL and AC3 stained sections from the frontal
cortex demonstrated a low number of damaged and apoptotic cells in
comparison to ketamine-treated brains. The lesions were
characterized by a mild multifocal amount of necrolytic debris,
degenerate axons and cell bodies and apoptotic nuclei of the 1st
and 2nd layers of cortex. The same cell types were involved as was
seen with ketamine, only the numbers were markedly reduced in
comparison to ketamine. Their incidence and severity was also less
then that seen with the higher dose of dexmedetomidine.
[0263] In Group 4, the high dose dexmedetomidine group, examination
of HE, Silver, TUNEL and AC3 stained sections from the frontal
cortex demonstrated a low number of damaged and apoptotic cells
that was increased in comparison to ketamine-treated brains. The
lesions were characterized by a mild multifocal amount of
necrolytic debris, degenerate axons and cell bodies and apoptotic
nuclei of the 1st and 2nd layers of cortex. The same cell types
were involved as was seen with ketamine, only the numbers were
markedly reduced in comparison to ketamine.
[0264] The results from this study indicate that treatment with 20
mg/kg IM+20-50 mg/kg/hr ketamine was associated with marked
neuroapoptosis and cellular damage with necrosis primarily in
layers I and II of the cortex. This was a diffuse and uniform
multifocal to diffuse lesion extending through the frontal cortex
including layers I-VI, but primarily in layers 1 and 2. There were
no significant neuroapoptotic lesions present in the untreated
group. In animals receiving dexmedetomidine there was no to minimal
neuroapoptosis present following either 3 ug/kg.times.10 min+3
ug/kg/hr or 30 ug/kg.times.30 min+3 ug/kg/hr. Lesions were less
severe in the low-dose animals, indicative of a dose response and
the lesions were clearly much less severe than the ketamine treated
animals. These findings suggest that dexmedetomidine is not
associated with significant neuroapoptosis. In particular, these
findings suggest that dexmedetomidine is not associated with
significant neuroapoptosis at the low dose.
Example 5: Pharmacokinetics of Dexmedetomidine in Pediatric
Patients Aged 1 Month to 24 Months
[0265] The present study characterizes the pharmacokinetic and
pharmacodynamic profile of dexmedetomidine administered as an
intravenous (IV) loading dose followed by a continuous IV infusion
in pediatric subjects.
[0266] A 36-patient, open-label, single center, escalating dose
study of dexmedetomidine was conducted on pediatric subjects who
were postoperative from cardiac surgery. The study investigated the
pharmacokinetics and pharmacodynamics of dexmedetomidine. The
subjects were 1 month to 24 months old with tracheal intubation or
mechanical ventilation in the immediate postoperative period, and
planned tracheal extubation within 24 hours after surgery. The
subjects received one of the doses given in Table 35 below.
[0267] The primary objectives of this study were as follows: [0268]
To define the pharmacokinetics of increasing doses of
dexmedetomidine administered as an intravenous bolus followed by a
continuous IV infusion (CIVI) in infants who were postoperative
from cardiac surgery. [0269] To describe the pharmacodynamic
effects of dexmedetomidine in infants (age: 1 month to 2 years) who
were post-operative surgical patients during the 24-hour period
prior to, and during, extubation.
[0270] The secondary objectives were as follows: [0271] To obtain
correlation data on the relationship between level of sedation and
dexmedetomidine plasma drug concentration in infants post-operative
from cardiac surgery and [0272] To evaluate safety in the 1 month
to 2 year old patient population.
[0273] This was a single center, phase I dose escalation
pharmacokinetic study of a single bolus dose of dexmedetomidine
followed by a continuous infusion for up to 24 hours, in infants
who were immediately post-operative from cardiac surgery and
required tracheal intubation with mechanical ventilation in the
post-operative period. This dose-response study of dexmedetomidine
in infants consisted of two phases: a screening/enrollment phase,
and a dose escalation phase.
[0274] Patients whose parents or legal guardians provided informed
consent were screened within 7 days prior to enrollment. The
screening/enrollment phase was performed first. Infants (1 month to
2 years of age) who were pre-operative from surgery were screened.
Infants were eligible for the study if they were post-operative
from cardiac surgery and required mechanical ventilation in the
post-operative period with tracheal extubation expected within the
first 24 post-operative hours. Enrollment criteria had to have been
met within 7 days prior to enrollment. The dose escalation phase
followed the screening/enrollment phase. All patients received 4
mg/kg orally of pentobarbital, an intra-operative IV dose of 20
.mu.g/kg of fentanyl, an IV dose of 0.2 mg/kg of pancuronium on
induction and another 0.2 mg/kg on institution of bypass. Three
bolus and infusion dose combinations of dexmedetomidine were
administered as follows: cohorts of 12 patients each received
either low-dose dexmedetomidine (0.35 .mu.g/kg IV bolus
administered over 10 minutes, 0.25 .mu.g/kg/hour continuous IV
infusion), moderate-dose dexmedetomidine (0.7 .mu.g/kg IV bolus
administered over 10 minutes, 0.5 .mu.g/kg/hour continuous IV
infusion) or high-dose dexmedetomidine (1 .mu.g/kg IV bolus over 10
minutes, 0.75 .mu.g/kg/hour continuous IV infusion).
Dexmedetomidine infusion was continued during the extubation
process and tracheal extubation occurred when patients had met the
respiratory criteria. Inter-patient dose escalation is shown in
Table 35.
TABLE-US-00037 TABLE 35 Inter-Patient Escalation Continuous IV Dose
Loading Dose Infusion Rate Level (.mu.g/kg) (.mu.g/kg/hour) 1 0.35
0.25 2 0.7 0.5 3 1 0.75
[0275] Twelve patients were studied at each dose level. If more
than 2 patients at a dose level experienced a dose-limiting
toxicity (DLT) that was possibly, probably, or definitely related
to study drug, the maximum tolerated dose (MTD) for the drug would
have been exceeded and no additional patients would be studied at
that dose level. If the MTD was exceeded at the first dose level,
then the subsequent cohort of patients would be treated at a
loading dose of 0.25 .mu.g/kg and an infusion of 0.14
.mu.g/kg/hour. If the MTD had been exceeded at the second or third
dose levels, enrollment to the protocol would have been
stopped.
[0276] The decision to escalate the dose was based on the review of
safety and pharmacokinetic data for all patients in the previous
cohort. If the median clearance was less than 70% of that reported
in the adult population (35 L/hour), then accrual to the study was
stopped.
[0277] This dose escalation study included dose cohorts of 1) 0.35
.mu.g/kg bolus, 0.25 .mu.g/kg/hour infusion; 2) 0.7 .mu.g/kg bolus,
0.5 .mu.g/kg/hour infusion; 3) or 1 .mu.g/kg bolus, 0.75
.mu.g/kg/hour infusion. This study provided pharmacokinetic data
that would allow for improved dosing recommendations in a
critically ill population of patients (infants who were
post-operative from cardiac surgery and required mechanical
ventilation in the post-operative period). This population of
patients included, but was not limited to, infants diagnosed with
Teratology of Fallot, atrio-ventricular canal defects, ventricular
septal defects, coarctation of the aorta, bi-directional glen,
hemi-fontan, and fontan completions. The Bispectral Index Scale
(BIS) was used to measure sedation, and explore the utility of a
non-invasive measurement of sedation in infants who were
postoperative from cardiac surgery. Also, this study was designed
to obtain preliminary data on the relationship between the level of
sedation and dexmedetomidine plasma drug concentration in infants
postoperative from cardiac surgery. Safety was also evaluated in
this study.
[0278] A patient was eligible for study participation if he or she
met the following criteria: was .gtoreq.1 month and .ltoreq.24
months of age; was post-operative from cardiac surgery with
tracheal intubation/mechanical ventilation in the immediate
post-operative period; had planned tracheal extubation within 24
hours post-operatively; adequate renal function (defined as serum
creatinine.ltoreq.0.6 mg/dL at age 1 month to 12 months or serum
creatinine.ltoreq.1.0 mg/dL at age>12 months to 24 months);
adequate liver function (defined as total bilirubin.ltoreq.1.5
mg/dL and serum glutamic pyruvic transaminase (SGPT).ltoreq.165 U/L
for 1 month to 12 months and .ltoreq.90 U/L for >12 months to 24
months); had isolated heart surgery; and all parents or legal
guardians of the patient signed a written informed consent.
[0279] A patient was not eligible for study participation if he or
she met any of the following criteria: received another
investigational drug within the past 30 days or received continuous
infusions of muscle relaxants in the post-operative setting; had a
positive blood culture without a subsequent negative culture or
other evidence of ongoing serious infection; in the opinion of the
investigator, would not be able to comply with the safety
monitoring requirements of the study; showed signs or symptoms of
elevated intracranial pressure (including, but not limited to,
Cushing's triad (hypertension, bradycardia, and bradypnea),
lethargy, bulging fontanelle, and seizures; had post-operative
hypotension based on age (1 month to 2 months: systolic.ltoreq.45
mm Hg, diastolic.ltoreq.25 mm Hg, or mean arterial blood
pressure.ltoreq.35 mm Hg; >2 months to 6 months:
systolic.ltoreq.55 mm Hg, diastolic.ltoreq.35 mm Hg, or mean
arterial blood pressure.ltoreq.45 mm Hg; and >6 months to 24
months: systolic.ltoreq.65 mm Hg, diastolic.ltoreq.45 mm Hg, or
mean arterial blood pressure.ltoreq.55 mm Hg); or had pre-existing
bradycardia based on age (1 month to 2 months: heart rate.ltoreq.90
bpm; 2 months to 12 months: heart rate.ltoreq.80 bpm; >12 months
to 24 months: heart rate.ltoreq.70 bpm); had a heart block;
weighed<5 kg; or who, in the opinion of the investigator, was
not an appropriate candidate for an investigational drug study.
[0280] Patients were discontinued from the study if any of the
following occurred: there was a DLT, including bradycardia,
hypotension, oversedation, or serious adverse effect; the patient's
parent/guardian refused further protocol therapy; non-compliance
that, in the opinion of the investigator, did not allow for ongoing
participation in the study; and the investigator judged that
withdrawal was in the best interest of the patient.
[0281] Patients who were off protocol therapy were followed until
they met the off-study criteria which was defined as 30 days after
the last dose of the investigational agent, death, lost to follow
up, or withdrawal of consent for any further data submission.
Follow-up data were required unless consent was withdrawn.
[0282] Eligible patients, who met all the inclusion criteria and
none of the exclusion criteria, received 4 mg/kg orally of
pentobarbital premedication, an intra-operative dose of 20 .mu.g/kg
of fentanyl, 0.2 mg/kg of pancuronium on induction and another 0.2
mg/kg on institution of bypass as intra-operative anesthetic. This
was followed by administration of study drug where dexmedetomidine
(0.35 .mu.g/kg, 0.7 .mu.g/kg, or 1 .mu.g/kg) was administered as an
IV loading dose over 10 minutes followed by a continuous
maintenance IV infusion of 0.25 .mu.g/kg/hour, 0.5 .mu.g/kg/hour,
or 0.75 .mu.g/kg/hour. Patients received one of three
loading/maintenance regimens of dexmedetomidine as follows: cohorts
of 12 patients received low-dose dexmedetomidine (0.35 .mu.g/kg
bolus, 0.25 .mu.g/kg/hour infusion), moderate-dose (0.7 .mu.g/kg
bolus, 0.5 .mu.g/kg/hour infusion) or high-dose dexmedetomidine (1
.mu.g/kg bolus, 0.75 .mu.g/kg/hour infusion). Dexmedetomidine
infusion was continued during the extubation process and tracheal
extubation occurred when patients had met the respiratory
criteria.
[0283] Study drug consisted of the test drug (investigational
product), Precedex.RTM. (dexmedetomidine HCl injection), 118 .mu.g
of dexmedetomidine and 9 .mu.g of sodium chloride in water, IV. The
study drug was supplied as a clear, colorless, isotonic solution
with a pH of 4.5. The solution was preservative free and contained
no additives or chemical stabilizers. It was freely soluble in
water with a pKa of 7. Dexmedetomidine was obtained by commercial
supply for this study and was stored in the Pharmacy at a
controlled room temperature of 15.degree. C. to 30.degree. C.
(59.degree. F. to 86.degree. F.). Freezing was avoided.
[0284] Patients who met the selection criteria were enrolled in the
study. Thirty-eight patients were enrolled in this study.
Thirty-six patients completed the study drug infusion: 12 patients
in each of the low, moderate and high dose cohorts. Randomization
was not conducted in this study; this was a dose escalation study
of a single bolus of dexmedetomidine followed by a continuous IV
infusion for up to 24 hours in infants immediately
post-operatively.
[0285] The study drug, dexmedetomidine, was administered as a bolus
dose over 10 minutes followed by a continuous IV infusion to
patients who returned from the operating room tracheally intubated,
with planned tracheal extubation within 24 hours. Twelve patients
were studied at each dose level. If more than 2 patients at a dose
level experienced a DLT that was possibly, probably, or definitely
attributable to the study drug, the MTD for the drug was considered
to be exceeded and no additional patients were studied at that dose
level. If the MTD was exceeded at the first dose level, then the
subsequent cohort of patients were to be treated at a loading dose
of 0.25 .mu.g/kg and an infusion of 0.14 .mu.g/kg/hr. If the MTD
had been exceeded at the second or third dose levels, enrollment to
the protocol would have been stopped. The dose levels were studied
consecutively with pharmacokinetic analysis following the
completion of each dose level. If the median clearance was less
than 70% of that reported in the adult population (35 L/hr),
accrual to the study was stopped. This was an unblinded study.
[0286] Patients were not allowed to receive continuous infusions of
muscle relaxants in the postoperative setting. Additional sedation
or analgesia in the form of fentanyl (0.25 to 1 .mu.g/kg/dose),
morphine (10 to 100 .mu.g/kg/dose), or midazolam (10 to 100
.mu.g/kg/dose) was allowed for those patients who were identified
by the clinical team as being "under sedated". Any additional
sedation medications, the dose, route of administration, and date
and time of administration were recorded. Any medications taken
during the study, other than the study drug, were recorded.
[0287] It is statistically reliable and clinically relevant to use
power assessment and confidence intervals to detect dose
proportionality, in which dose increases with an expected
proportional increase in both AUC and C.sub.max. The University of
Michigan Sedation Score (UMSS) is a validated pediatric sedation
scale and is used as a pharmacodynamic measurement for the Example
5 study. Other pharmacokinetic, PD, and safety measurements in this
study are widely used and are generally recognized as reliable,
accurate, and relevant for the study. The pharmacokinetic variables
for assessment included: observed peak plasma concentration
(C.sub.max), time of observed peak plasma concentration
(T.sub.max), area under the plasma concentration-time curve from
time zero to the last quantifiable time point (AUC.sub.0-t), area
under the plasma concentration-time curve from time zero to
infinity (AUC.sub.0-inf), terminal elimination rate constant
(.lamda.z), terminal half-life (t.sub.1/2), end of infusion
concentration (steady state, C.sub.ss), plasma clearance (Cl),
weight adjusted clearance (Cl.sub.w), volume of distribution
(V.sub.d), and weight adjusted volume of distribution (V.sub.dw).
The primary PD variables assessed the level of sedation using BIS
and the University of Michigan Sedation Scale Safety variables
included exposure to study drug, adverse events (adverse effects),
hepatotoxicity, DLT, laboratory results, vital signs, use of
concomitant medication, and 12-lead electrocardiogram.
[0288] For the drug concentration measurements, approximately 14 mL
of blood (14 samples per patient) were collected from each patient.
Blood samples (1 mL) were collected in heparinized tubes for
pharmacokinetic evaluation of plasma dexmedetomidine. For the low
dose treatment group, blood samples were collected at time zero for
the bolus dose, at the end of the bolus dose, at 0.5 hours after
start of infusion, at the end of the maintenance infusion, and at
0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after the end of the
maintenance infusion. For the remaining cohorts, blood samples were
collected prior to the bolus dose, in close proximity to 0.5, 1, 2,
and 4 to 6 hours after the start of the infusion, at 15-30 minutes
prior to end of infusion (EOI), and at 0.25, 0.5, 1, 2, 4, 8, 12,
and 15 to 18 hours after the EOI. Samples were collected from a
different site than that of the infusion site. Samples were not
collected from the 2nd lumen of the multi-lumen catheter through
which the drug was administered. The exact time that the sample was
collected along with the exact time that the drug was administered
were recorded. Plasma was separated and stored at -80.degree. C.
until assayed. The lower limit of quantification in plasma is
.ltoreq.4.24 pg/mL for dexmedetomidine. Each heparinized tube was
labeled with the patient's study number, the study identification
number, and the date and time that the sample was collected. Data
were recorded on the Pharmacokinetic Study Form, which accompanied
the sample.
[0289] The primary pharmacokinetic evaluation was to define the
pharmacokinetics of increasing doses of dexmedetomidine
administered as an IV bolus followed by a continuous IV infusion in
infants who were postoperative from cardiac surgery. Data from all
fully evaluable patients (those receiving at least 2 hours of
dexmedetomidine infusion) were included in the analysis.
[0290] The pharmacodynamic assessments monitored continuously every
hour until 24 hours after the discontinuation of the infusion
included heart rate, blood pressure, mean arterial blood pressure,
cardiac rhythm, oxygen saturation, and respiratory rate. The
Bispectral Index Scale (BIS, Aspect Medical Systems, Natick, Mass.)
and the University of Michigan Sedation Scale (UMSS) were used to
assess the level of sedation.
[0291] The Bispectral Index Scale (BIS) integrates various
electroencephalogram (EEG) descriptors into a single variable. The
BIS readout is a dimensionless number scaled from 100 to 0, with
100 representing an awake EEG and zero representing complete
electrical silence (cortical suppression). BIS and hypnotic drug
dose have been shown to correspond to a statistically significant,
linear, monotonic fashion during clinical trials, with BIS
decreasing as the hypnotic dose is increased. The BIS monitor was
applied to the patient's forehead prior to the bolus dose, and
remained until the EOL A member of the clinical team periodically
did a sensor check to be sure signal quality and proper sensor
application/adhesion were maintained. BIS values, with the
exception of the Signal Quality Index (SQI) were blinded.
Pre-stimulation BIS values were recorded for sedation assessments
(or during non-stimulated times). The maximal BIS reading during
stimulation was also recorded. The "resting" BIS values or those at
non-stimulated times, along with the change in BIS with
stimulation, were valuable in assessing not only the sedation drug
effect, but also the analgesic properties of the drug, and thus
provided better data to assess the PD of the drug. The
investigators were blinded to the BIS readout until after the study
was completed. The maximum BIS readout and the corresponding SQI
were recorded for each hour that the patient was on study. The BIS
sensor was removed from the patient's head after the infusion had
been discontinued, and the patient had been declared awake by the
clinical care team.
[0292] The UMSS is a simple, valid and reliable tool that
facilitates rapid and frequent assessment and documentation of
depth of sedation in children. The UMSS is a simple observational
tool that assesses the level of alertness on a 5-point scale
ranging from 1 (wide awake) to 5 (unarousable with deep
stimulation). The UMSS score was assessed by the clinical nurse
caring for the patient, and recorded every hour until the BIS
sensor was removed.
[0293] Adverse events were reported in a routine manner at
scheduled times during the trial. Certain adverse effects were
reported in an expedited manner to allow for optimal monitoring of
patient safety and care. Adverse events were reviewed at bi-weekly
meetings by the principal investigator (PI), co-PI, and study
coordinator. Events were classified as either adverse effects or
serious adverse effects.
[0294] An adverse effect was defined as any untoward medical
occurrence that presented itself during treatment or administration
with a pharmaceutical product and which may or may not have a
causal relationship with the treatment. A treatment-emergent
adverse event (treatment-emergent adverse effect) was defined as
any adverse effect with onset or worsening reported by a patient
from the time that the first dose of study drug was administered
until 24 hours had elapsed following discontinuation of study drug
administration. An adverse effect that occurred during the
treatment period was defined as any adverse effect with onset or
worsening reported by a patient from the date/time of the start of
study drug administration until the data/time of study drug
discontinuation. An adverse effect that occurred post study drug
was defined as any adverse effect with onset or worsening reported
by the patient at a date/time which was later than the date/time of
study drug discontinuation within the specific period. Adverse
events were also classified by severity (mild, moderate, or
severe). A serious adverse effect was defined as any untoward
medical occurrence that at any dose resulted in death, was life
threatening, required inpatient hospitalization or prolongation of
existing hospitalization, created persistent or significant
disability/incapacity, or a congenital anomaly/birth defect.
MedWatch reports were completed for each event. Events were
classified by the treating clinician and study coordinator. Events
were classified as unlikely, possibly, or probably related to the
study drug and either previously described (expected), or
undescribed (unexpected). The PI was notified by pager or telephone
of any serious adverse effects. All drug-related and previously
undescribed toxicities were reviewed within 24 hours by the PI.
Serious adverse effects that were expected because of the surgical
procedure did not require expedited review and were reviewed
bi-weekly. Previously undescribed toxicities and all serious
adverse effects were reported to the IRB in writing by the
investigator within 72 hours of the event. A letter summarized any
adverse reactions or events that occurred, and the event outcome
was described. If more than one unexpected or previously described
serious adverse effect attributable to study drug was observed,
accrual to the protocol was suspended. An ad hoc committee
comprising the PI, subspecialty lead investigator, and at least 2
subspecialists not participating in the trial were convened by the
PI within 24 hours of the second event. An assessment of the risks
to patients were made, and a recommendation to continue with the
study or close the trial were made to the IRB for review. If a
decision was made to continue with the trial, the modifications to
the protocol, the updated assessment of risks and benefits, and a
modified informed consent were to be submitted to the IRB.
[0295] A dose limiting toxicity (DLT) was defined as any of the
events that are possibly, probably, or definitely attributable to
dexmedetomidine and fall under the following: [0296] bradycardia
defined by age: heart rate.ltoreq.80 bpm (1 month to 2 months);
heart rate.ltoreq.70 bpm (>2 months to 12 months); heart
rate.ltoreq.60 bpm (>12 months to 24 months) [0297] hypotension
defined by age: [0298] systolic.ltoreq.40 mm Hg,
diastolic.ltoreq.20 mm Hg, or mean arterial blood pressure
(MAP).ltoreq.30 mm Hg (1 month to 2 months) [0299]
systolic.ltoreq.50 mm Hg, diastolic.ltoreq.30 mm Hg, or
MAP.ltoreq.40 mm Hg (>2 months to 6 months) [0300]
systolic.ltoreq.60 mm Hg, diastolic.ltoreq.40 mm Hg, or
MAP.ltoreq.50 mm Hg (>12 months to 24 months) [0301] bradypnea:
respiratory rate.ltoreq.14 bpm in extubated patients [0302]
oversedation deemed clinically relevant by the clinical care
providers or requiring intervention. Clinical signs included
difficulty arousing with moderate stimulation, bradypnea
(respiratory rate.ltoreq.14), bradycardia, and hypotension and
[0303] serious adverse event.
[0304] Laboratory data for the clinical laboratory tests was
collected as standard of care were also reviewed during the study
and included arterial blood gas, lactate, basic metabolic panel,
magnesium, phosphorus, coagulation panel, liver function panel, and
complete blood count. Approximately 14 mL of blood was collected
from each patient for the clinical laboratory tests during the
study.
[0305] Additional safety assessments were carried out including
physical examination, 12-lead electrocardiogram, hepatotoxicity,
and sedation/analgesia supplemental medication titration.
[0306] The statistical analyses were performed using SAS, version
9.1. Pharmacokinetic parameters were determined by
non-compartmental analysis using WinNonlin Pro Version 5.1. All
statistical tests were two-sided, and p-values.ltoreq.0.05 were
considered statistically significant (after rounding to 4 decimal
places), unless specified otherwise. Descriptive statistics (number
of patients [N], mean, median, standard deviation (SD), minimum,
and maximum) were used to summarize continuous variables.
Coefficient of variation (CV) was calculated for continuous
pharmacokinetic variables. For T.sub.max (a discrete variable), N,
median, minimum and maximum were displayed. The mean and median
were displayed to one decimal place more than the raw value. For
categorical variables, N and percent were shown. All percentages
were reported to one decimal place. Patient listings of all
collected and recorded data as well as derived variables were
presented. Changes noted between analyses defined in the protocol
and those defined in the SAP included:
[0307] There were two discrepancies between the study and the
protocol. One regarded the definition of a DLT. The study defines
DLT to include bradycardia and hypotension defined by age, and
clinically relevant oversedation, and serious adverse effects as
DLTs. The protocol included only bradycardia defined by age,
hypotension defined by age, and bradypnea defined by respiratory
rate.
[0308] Another discrepancy was in regards to the collection of ECG
data. The protocol stated that ECGs were obtained pre- and
post-treatment and compared for evidence of new ischemia. ECG
charts and QT intervals were not available and there was no plan to
analyze the ECG data.
[0309] The protocol referenced collection of plasma samples for
pharmacogenomic testing; however, no samples were collected for
pharmacogenomic testing or analysis.
[0310] Four patient populations were defined in this study.
[0311] Enrolled Population: All patients who signed inform consent
were in the Enrolled Population.
[0312] Intent-to-Treat (ITT) Population: Patients who were treated
and were protocol compliant were included in the ITT
Population.
[0313] Safety Population: All patients who received study drug were
included in the Safety Population. This population was used in all
safety analyses.
[0314] Pharmacokinetic Analysis Population: All patients who
received at least 2 hours of dexmedetomidine infusion were included
in the Pharmacokinetic Analysis Population.
[0315] Plasma samples were assayed for dexmedetomidine
concentrations. The following parameters were calculated for each
patient: AUC.sub.0-t, AUC.sub.0-inf, C.sub.max, T.sub.max, Cl,
Cl.sub.w, V.sub.d, weight adjusted volume of distribution
(V.sub.dw), .lamda.z, t.sub.1/2, and C.sub.ss. Area under the
plasma concentration-time curve (AUC) and C.sub.max were the
primary pharmacokinetic parameters.
[0316] Model-independent methods were used by Hospira to determine
the pharmacokinetic parameters described above using
Non-Compartmental Analysis of WinNonlin version 5.1 (Pharsight,
Mountain View Calif., USA). Summary statistics for these parameters
were tabulated. Geometric means and coefficients of variation were
presented for AUC and C.sub.max.
[0317] An assessment of dose proportionality was made for AUC and
C.sub.max among the dose levels administered within an age group
and overall. The Power Analysis approach and data visualization
techniques were used for this assessment.
[0318] Dose proportionality was evaluated statistically using the
Power Model. The Power Model has the form:
parameter=a(dose)b.times.random error, where a and b are the
coefficient and exponent, respectively of the equation. The power
model was analyzed using linear regression after log transformation
using the following equation:
ln(parameter)=ln(a)+b.times.ln(dose)+random error. Dose
proportionality was concluded if the 95% confidence interval (CI)
for b included 1 or, b=0 (HO) was not rejected when applied to
dose-normalized parameters.
[0319] Data visualization techniques included the plotting of
weight adjusted clearance over age, AUC, and C.sub.max against
administered dose to determine if trends were present in the data
that would indicate the need for further assessment.
[0320] An exploratory assessment of a potential pharmacokinetic/PD
relationship was undertaken. The relationship of PD parameters such
as sedation level or need for rescue sedation medication and
pharmacokinetic parameters AUC or C.sub.max were explored.
[0321] The pharmacodynamic analysis was summarized by dose level
for ITT and Pharmacokinetic Populations. The PD assessments
contained sedation levels and vital signs that were monitored
continuously every hour until 24 hours after the discontinuation of
the infusion. Parameters included heart rate, blood pressure, MAP,
cardiac rhythm, oxygen saturation and respiratory rate. Descriptive
statistics (arithmetic mean, SD, median, minimum and maximum) were
calculated for quantitative PD data as well as for the changes from
Baseline by dose level. The BIS and the UMSS were used to assess
the level of sedation.
[0322] The UMSS score was summarized by count and percentage of
patients for each sedation level by dose level. The number and
percentage of patients using fentanyl, morphine, or midazolam
during study drug administration was summarized by dose level and
treatment differences were assessed by Fisher's Exact Test. The
total amount of fentanyl, morphine, and midazolam was summarized
descriptively for each dose level, and by time period after the
start of infusion in each dose level. The time frame was to be
analyzed for total amount of sedation medication after start of
infusion at 4 hours, 4 to 8 hours, 8 to 12 hours, and 0 to 24
hours. Exploratory analysis was performed for the relationship
between exposure of pharmacokinetic parameters (such as AUC,
C.sub.max, or C.sub.ss) and usage of sedation medication (such as
total dose).
[0323] Descriptive statistics were used to summarize vital signs
measurements for heart rate, blood pressure, temperature, mean
arterial blood pressure (MAP), respiratory rate, and saturation of
peripheral oxygen (SpO.sub.2) in a dose-dependent manner with time
compared with Baseline. Treatment differences in the mean change
from Baseline on each timepoint were assessed by one-way analysis
of variance (ANOVA) with treatment factor in the model.
[0324] All safety data were listed by patients. Safety data
included exposure of study drug, adverse effects, cardiac ischemia,
liver function tests, DLT assessments, clinical laboratory
evaluations, physical exams, and the use of concomitant
medications. Descriptive statistics (arithmetic mean, SD, median,
minimum and maximum) were calculated for quantitative safety data
as well as for the difference from Baseline, when appropriate.
[0325] The exposure to study medication was quantified according to
the bolus dose and maintenance dose of study drug administered.
Loading dose (or bolus dose) was summarized using the parameters of
total dose and duration of dose. Maintenance dose was summarized
using the total dose, and total duration of dose (in hours). Total
dose equaled loading dose+CIVI rate.times.duration of dose.
Duration of dose and total hours of dose were both calculated using
time of last administration minus time of first administration,
excluding interruptions. The patient's weight was carried forward
to use in dose calculation.
[0326] Adverse events were coded using the most updated version of
the Medical Dictionary for Regulatory Activities (MedDRA Version
11.0) available and summarized by dose level for the number of
patients reporting the adverse effect and the number of adverse
effects reported. A by-patient adverse effect data listing included
verbatim term, coded term, treatment group, severity, and
relationship to treatment provided. Serious adverse events
associated with death and adverse effects leading to
discontinuation of study drug were also summarized and listed. A
treatment-emergent adverse effect was defined as any adverse effect
with onset or worsening reported by a patient from the time that
the first dose of study drug was administered until 24 hours had
elapsed following discontinuation of the study drug. For summaries
by severity, if a patient had multiple events occurring in the same
system organ class (SOC) or same preferred term, then the event
with the highest severity was summarized. Any adverse effect with a
missing severity was summarized as severe. Similar methodology was
applied to relationship to study drug.
[0327] Laboratory test results for change from Baseline were
tabulated descriptively by treatment. All laboratory values outside
the normal range were flagged in the data listings. Patients were
evaluated by body system and were categorized as normal or
abnormal. Since ECG charts and QT intervals were not available, ECG
data were not analyzed. A summary of hepatotoxicity was presented
by number and percentage of patients by dose level in each
scheduled visit.
[0328] The sample size was based on the determination of the
pharmacokinetic profile of dexmedetomidine. Based on an estimated
inter-patient variability of 50% for steady state concentration, a
sample size of 36 evaluable patients was to be sufficient to detect
a difference (alpha 0.05, power 80%) for AUC and C.sub.ss between
the three dosing groups. Twelve evaluable patients were to be
enrolled into each dose group. Based on clinical intensive care
unit (CICU) patient census, it was estimated that 15 months would
be required to complete enrollment.
[0329] Patient disposition is summarized in Table 36.
TABLE-US-00038 TABLE 36 Disposition of Patients-Enrolled Patients
Low Moderate High Dose.sup.a Dose.sup.b Dose.sup.c Total Patients
(%) N = 12 N = 12 N = 14 N = 38 Patients who 12 (100.0) 12 (100.0)
12 (85.7) 36 (94.7) completed treatment Patients who 1 (8.3) 0 2
(14.3).sup.d 3 (7.9) prematurely discontinued study Patients in
Safety 12 (100.0) 12 (100.0) 14 (100.0) 38 Population (100.0)
Patients in Intent- 12 (100.0) 12 (100.0) 12 (85.7) 36 (94.7)
to-Treat Population Patients in 12 (100.0) 12 (100.0) 12 (85.7) 36
(94.7) Pharmacokinetic Population .sup.aLow-dose dexmedetomidine
(0.35 .mu.g/kg bolus, 0.25 .mu.g/kg/hour infusion).
.sup.bModerate-dose dexmedetomidine (0.7 .mu.g/kg bolus, 0.5
.mu.g/kg/hour infusion). .sup.cHigh-dose dexmedetomidine (1.0
.mu.g/kg bolus, 0.75 .mu.g/kg/hour infusion). .sup.dTwo patients in
the high dexmedetomidine dose group discontinued the study and were
not included in the ITT Population.
[0330] Thirty-eight patients were enrolled into the study and
assigned into one of 3 treatment groups: low-dose dexmedetomidine
(0.35 .mu.g/kg bolus, 0.25 .mu.g/kg/hour infusion), moderate-dose
dexmedetomidine (0.7 .mu.g/kg bolus, 0.5 .mu.g/kg/hour infusion),
or high-dose dexmedetomidine (1.0 .mu.g/kg bolus, 0.75
.mu.g/kg/hour infusion). Of the 38 enrolled patients, 3 (7.9%)
discontinued the study prematurely. One patient in the low-dose
dexmedetomidine treatment group completed study drug infusion and
subsequently discontinued the study. Two patients in the high-dose
dexmedetomidine treatment group discontinued the study prematurely;
these patients were not included in the Pharmacokinetic Population.
36 of the 38 enrolled patients (94.7%) completed treatment.
[0331] All 38 patients enrolled into the study received at least 1
dose of study medication and were included in the Safety
Population. Thirty-six patients received at least 2 hours of
dexmedetomidine infusion and had sufficient concentration data to
calculate the primary pharmacokinetic parameters; these patients
were included in the Pharmacokinetic Population. Thirty-six
patients in the ITT Population completed treatment.
[0332] Patients who prematurely discontinued treatment were
recorded. Protocol deviations were also recorded. Demographics of
the patient population were collected as well as medical and birth
history. Prior and concomitant medications were also recorded.
[0333] Summary statistics for the dexmedetomidine loading doses and
maintenance infusion doses are shown in Table 37.
TABLE-US-00039 TABLE 37 Summary Statistics of Dosing-Related Data
0.35 .mu.g/kg + 0.70 .mu.g/kg + 1.00 .mu.g/kg + Dose-Related
Variable 0.25 .mu.g/kg/h 0.50 .mu.g/kg/h 0.75 .mu.g/kg/h Loading
dose (ng) Mean (SD) 2782.000 5144.417 7468.333 (701.169) (1169.842)
(1759.374) Median 2620.000 4907.000 6850.000 Min, Max 1876.00,
3787.00, 5100.00, 4165.00 7070.0 11200.00 n 12 12 12 Maintenance
infusion Mean (SD) 17699.500 34790.417 57580.000 dose (ng)
(14649.792) (18282.909) (29129.275) Median 13638.000 31060.500
45864.000 Min, Max 7375.00, 10443.00, 2669.00, 61707.00 68425.00
117300.00 n 12 12 12 Total dose (ng) Mean (SD) 20481.500 39934.833
65048.333 (14922.818) (18364.830) (28941.225) Median 16589.500
35950.000 53799.000 Min, Max 9853.00, 15427.00, 35196.00, 65347.00
73255.00 124200.00 n 12 12 12 Loading infusion Mean (SD) 0.182
(0.021) 0.168 (0.021) 0.183 (0.038) duration (h) Median 0.167 0.167
0.183 Min, Max 0.17, 0.22 0.12, 0.20 0.12, 0.27 n 12 12 12
Maintenance infusion Mean (SD) 8.901 (6.055) 9.853 (6.055) 10.961
(6.635) duration (h) Median 6.610 8.619 8.708 Min, Max 4.17, 23.75
2.94, 23.82 4.18, 22.65 n 12 12 12 Time between start of doses Mean
(SD) 14.500 (2.646) 11.917 (2.610) 12.833 (1.899) (min) Median
14.500 11.500 13.000 Min, Max 11.00, 20.00 7.00, 17.00 10.00, 16.00
n 12 12 12 Time from end of 1.sup.st Mean (SD) 3.583 (2.429) 1.833
(2.167) 1.833 (1.403) to beginning of 2.sup.nd Median 3.00 1.500
2.000 infusion (min) Min, Max 1.00, 8.00 0.00, 7.00 0.00, 4.00 n 12
12 12
[0334] Two patients were excluded from the pharmacokinetic
analysis. Both patients were in the high dexmedetomidine dose
group. Thirty-six patients had sufficient concentration data to
calculate the pharmacokinetic parameters and were included in the
pharmacokinetic analysis set. Patients who were treated and
protocol compliant were included in the ITT Population. The
pharmacokinetic population and ITT included the same patients;
therefore, analysis for baseline characteristics was identical for
the ITT and the pharmacokinetic profiles. Safety profile was
analyzed for the Safety Population; thirty-eight patients received
at least 1 dose of study medication and were included in the Safety
Population.
[0335] The pharmacokinetic profile demonstrated linearity and dose
proportionality among 0.25, 0.50 and 0.75 .mu.g/kg/hour dose
levels; as dose increased, AUC and C.sub.max increased in
proportion. The mean doses were given as 20.5, 40.4, and 65.1 .mu.s
to 0.25, 0.50 and 0.75 .mu.g/kg/hour dose levels, respectively),
and as shown, exposure increased accordingly. AUC.sub.0-inf,
AUC.sub.0-t and C.sub.max of dexmedetomidine displayed positive
linearity among 0.25, 0.50 and 0.75 .mu.g/kg/hour dose levels. The
apparent t.sub.1/2 of dexmedetomidine was 2.33 hrs, 2.12 hrs, and
3.05 hrs for low, moderate, and high dose levels, respectively. The
geometric mean slope among the three dose levels and the 95%
confidence intervals were 1.263 (0.820, 1.706) for AUC.sub.0-inf,
and 0.898 (0.652, 1.143) for C.sub.max. A similar positive linear
trend was shown among the three age groups 1 to <6 months, 6 to
<12 months and 12 to 24 months.
[0336] The statistical analysis for assessing dose proportionality
for the three doses of dexmedetomidine is presented in Table 38.
Dose proportionality can be concluded for AUC.sub.0-t,
AUC.sub.0-inf, and C.sub.max given that the 95% CI for slope
included one for these parameters.
TABLE-US-00040 TABLE 38 Dose proportionality analysis of
dexmedetomidine pharmacokinetic parameters- PK population Geometric
Means Dexmedetomidine Dexmedetomidine Dexmedetomidine Low
Dose.sup.a Moderate Dose.sup.b High Dose.sup.c Slope.sup.d
Parameter (units) N = 12 N = 12 N = 12 (95% CIs) All PK Population
n 12 12 12 AUC.sub.0-t [hr*(ng/mL)] 1804.57 4163.01 7453.03 1.282
(0.835, 1.729) AUC.sub.0-inf [hr*(ng/mL)] 1851.13 4195.77 7492.29
1.263 (0.820, 1.706) C.sub.max (ng/mL) 277.59 460.66 760.76 0.898
(0.652, 1.143) Age 1 to <6 months n 5 4 3 AUC.sub.0-t
[hr*(ng/mL)] 1630.18 4171.58 7477.55 1.380 (0.631, 2.129)
AUC.sub.0-inf [hr*(ng/mL)] 1668.59 4209.96 7511.57 1.362 (0.621,
2.103) C.sub.max (ng/mL) 260.44 444.34 847.52 1.010 (0.455, 1.566)
Age 6 to <12 months n 4 6 7 AUC.sub.0-t [hr*(ng/mL)] 1542.76
4647.87 8392.11 1.541 (0.828, 2.255) AUC.sub.0-inf [hr*(ng/mL)]
1601.44 4675.95 8435.14 1.512 (0.804, 2.221) C.sub.max (ng/mL)
286.81 500.04 762.71 0.891 (0.489, 1.292) Age 12 to 24 months n 3 2
2 AUC.sub.0-t [hr*(ng/mL)] 2634.53 2979.07 4895.66 0.501 (-1.098,
2.100) AUC.sub.0-inf [hr*(ng/mL)] 2669.84 3010.96 4929.13 0.495
(-1.092, 2.083) C.sub.max (ng/mL) 295.55 387.09 641.22 0.654
(0.130, 1.177) .sup.aLow dose dexmedetomidine: 0.35 .mu.g/kg bolus,
0.25 .mu.g/kg/hour infusion. .sup.bModerate dose dexmedetomidine:
0.7 .mu.g/kg bolus, 0.5 .mu.g/kg/hour infusion. .sup.cHigh dose
dexmedetomidine: 1.0 .mu.g/kg bolus, 0.75 .mu.g/kg/hour infusion.
.sup.dEstimate slopes were computed from linear regression of log
(PK parameters) versus log (dose) over dose range. CI = confidence
interval
[0337] The predicted mean curve for AUC.sub.0-inf, AUC.sub.0-t, and
C.sub.max generated using the power fit model are presented in
FIGS. 34A-C.
[0338] A linear plot illustrating the mean dexmedetomidine
concentrations over time is shown in FIG. 35. The mean
dexmedetomidine concentration profiles (over time) for the three
treatment groups were similar, as illustrated in FIG. 35. Mean
plasma concentrations of dexmedetomidine tended to increase with
increased doses of dexmedetomidine. The highest mean plasma
concentrations were observed in the high-dose dexmedetomidine
treatment group. AUC and C.sub.max values increased with increasing
dose. Half-life values were independent of dose of level. The mean
half-life values for the low, moderate and high dose combinations
were 2.33, 2.12 and 3.05 hours, respectively. Pharmacokinetic
parameters of dexmedetomidine were summarized using descriptive
statistics and are presented in Table 39.
TABLE-US-00041 TABLE 39 Summary of Pharmacokinetic Parameters-ITT
Population Parameter/ Low Dose.sup.a Moderate Dose.sup.b High
Dose.sup.c Statistics N = 12 N = 12 N = 12 Primary Pharmacokinetic
Parameters AUC.sub.0-t (hr*ng/mL) Mean (SD) 2472.6 (2651.38) 4761.3
(2855.34) 8644.5 (5998.26) Median 1656.3 (721.9, 10420.7) 3443.5
(2364.2, 10891.8) 6910 (4400.6, 25990.7) (Min, Max) % CV 107.2 60.0
69.4 AUC.sub.0-inf (hr*ng/mL) Mean (SD) 2511.9 (2651.99) 4793.9
(2864.88) 8686.5 (6016.70) Median 1671.9 (735.0, 10458.3) 3469.1
(2389.8, 10961.0) 6948.0 (4441.0, 26078.4) (Min, Max) % CV 105.6
59.8 69.3 C.sub.max (hr/mL) Mean (SD) 300.1 (116.75) 479.6 (172.99)
786.4 (233.96) Median 296.5 (113, 473) 440.0 (339, 1010) 681.5
(602, 1340) (Min, Max) % CV 39 36 30 Secondary Pharmacokinetic
Parameters T.sub.max (hour).sup.d Median 2.39 (0.17, 18.98) 6.98
(1.20, 23.83) 6.13 (0.68, 22.55) (Min, Max) % CV 130.48 73.90 93.98
t.sub.1/2 (hour) Mean (SD) 2.33 (1.305) 2.12 (0.788) 3.05 (1.947)
Median 1.87 (1.14, 5.79) 2.02 (1.00, 3.89) 2.40 (1.65, 8.35) (Min,
Max) % CV 55.93 37.18 63.77 .lamda.z (1/hour) Mean (SD) 0.37
(0.151) 0.37 (0.141) 0.28 (0.108) Median 0.37 (0.12, 0.61) 0.34
(0.18, 0.69) 0.29 (0.08, 0.42) (Min, Max) % CV 41.34 38.17 38.19 Cl
(L/hour) Mean (SD) 10.24 (3.753) 9.27 (4.001) 8.49 (3.145) Median
9.74 (4.30, 17.12) 8.05 (4.44, 19.17) 7.84 (4.70, 15.17) (Min, Max)
% CV 36.66 43.17 37.02 Cl.sub.w (L/hour/kg) Mean (SD) 1.36 (0.637)
1.24 (0.362) 1.13 (0.278) Median 1.24 (0.60, 2.93) 1.24 (0.53,
2.05) 1.15 (0.69, 1.55) (Min, Max) % CV 46.90 29.27 24.62 V.sub.d
(L) Mean (SD) 30.54 (11.015) 27.20 (11.798) 36.02 (24.467) Median
29.09 (16.83, 54.09) 27.34 (11.97, 48.33) 27.53 (16.21, 95.34)
(Min, Max) % CV 36.06 43.38 67.93 V.sub.dw (L/kg) Mean (SD) 3.97
(1.432) 3.71 (1.693) 5.32 (4.865) Median 3.53 (2.01, 5.93) 3.36
(1.74, 7.75) 3.34 (2.70, 18.69) (Min, Max) % CV 36.05 45.60 91.53
.sup.aLow-dose dexmedetomidine: (0.35 .mu.g/kg bolus, 0.25
.mu.g/kg/hour infusion). .sup.bModerate-dose dexmedetomidine: (0.7
.mu.g/kg bolus, 0.5 .mu.g/kg/hour infusion). .sup.cHigh-dose
dexmedetomidine: (1.0 .mu.g/kg bolus, 0.75 .mu.g/kg/hour infusion).
.sup.dT.sub.max is presen ted as median only (minimum, maximum). CV
= coefficient of variation, ITT = Intent-to-Treat, max = maximum,
min = minimum, N, n = number of patients, SD = standard
deviation
[0339] Clearance and weight-adjusted clearance over age are
presented in FIG. 36. No noticeable increase or decrease in
clearance or weight-adjusted clearance for increasing age was
observed. No additional regression analysis was performed between
age and pharmacokinetic parameters.
[0340] A summary of the level of sedation, measured with the UMSS,
at each time point during the treatment period for the enrolled
population is presented in Table 40. Patients had deep sedation
(UMSS 3-4) from pre-dose to 2 hours after infusion, and maintained
a moderate level of sedation (UMSS 1-3) after 4 hours infusion
through the end of infusion for all dose levels. There was a
correlated relationship between plasma concentration and UMSS for
low dose 30 minutes after start of infusion, moderate dose 8 hours
after end of infusion, and high dose 30-15 minutes prior to end of
infusion and 60 minutes after end of infusion. With the UMSS, fewer
patients were categorized as "unarousable" at 1 hour post-infusion
as compared with Pre-bolus/Baseline, for all three dexmedetomidine
dose groups. After 1 hour of post-infusion of dexmedetomidine, the
level of sedation had decreased for all dose groups. Patients
became less sedated from the time of infusion to 6 hours
post-infusion. This was apparent with all 3 doses of
dexmedetomidine; the incidence of patients who were "unarousable"
at Pre-bolus/Baseline was 91.7%, 91.7%, and 83.3% for the low,
moderate, and high-dose dexmedetomidine groups, respectively. At
six hours post-infusion, the incidence of patients who were
"moderately sedated/somnolent" was 58.3%, 41.7%, and 50.0% for each
of the dexmedetomidine dose groups.
TABLE-US-00042 TABLE 40 Summary of Level of Sedation (UMSS) at
Selected Time Points During Treatment Period-ITT Population Number
(%) of Patients Low Moderate High Time Point Dose.sup.a Dose.sup.b
Dose.sup.c p- Characteristic N = 12 N = 12 N = 12 values.sup.d
Pre-bolus/Baseline 0.5788 Awake and alert 0 0 0 Minimally
sedated/Sleepy 1 (8.3) 0 0 Moderately sedated/ 0 0 0 Somnolent
Deeply sedated/Deep sleep 0 1 (8.3) 1 (8.3) Unarousable 11 (91.7)
11 (91.7) 10 (83.3) Post-bolus/Pre-infusion 0.4288 Awake and alert
0 0 0 Minimally sedated/Sleepy 1 (8.3) 0 0 Moderately sedated/ 0 1
(8.3) 0 Somnolent Deeply sedated/Deep sleep 1 (8.3) 2 (16.7) 0
Unarousable 10 (83.3) 9 (75.0) 11 (91.7) Number (%) of Patients
Post Infusion Hour 1 0.4880 Awake and alert 0 0 0 Minimally
sedated/Sleepy 1 (8.3) 0 0 Moderately sedated/ 1 (8.3) 0 2 (16.7)
Somnolent Deeply sedated/Deep sleep 1 (8.3) 3 (25.0) 1 (8.3)
Unarousable 9 (75.0) 9 (75.0) 8 (66.7) Post Infusion Hour 3 0.1834
Awake and alert 0 0 0 Minimally sedated/Sleepy 2 (16.7) 2 (16.7) 1
(8.3) Moderately sedated/ 3 (25.0) 2 (16.7) 4 (33.3) Somnolent
Deeply sedated/Deep sleep 7 (58.3) 3 (25.0) 2 (16.7) Unarousable 0
5 (41.7) 4 (33.3) Post Infusion Hour 6 0.8306 Awake and alert 0 1
(8.3) 1 (8.3) Minimally sedated/Sleepy 2 (16.7) 3 (25.0) 0
Moderately sedated/ 7 (58.3) 5 (41.7) 6 (50.0) Somnolent Deeply
sedated/Deep sleep 1 (8.3) 2 (16.7) 2 (16.7) Unarousable 1 (8.3) 1
(8.3) 1 (8.3) Post Infusion Hour 10 0.5512 Awake and alert 3 (25.0)
1 (8.3) 3 (25.0) Minimally sedated/Sleepy 2 (16.7) 4 (33.3) 2
(16.7) Moderately sedated/ 1 (8.3) 4 (33.3) 1 (8.3) Somnolent
Deeply sedated/Deep sleep 2 (16.7) 1 (8.3) 3 (25.0) Unarousable 0 1
(8.3) 0 Post Infusion Hour 14 0.5683 Awake and alert 2 (16.7) 2
(16.7) 4 (33.3) Minimally sedated/Sleepy 0 3 (25.0) 2 (16.7)
Moderately sedated/ 4 (33.3) 3 (25.0) 2 (16.7) Somnolent Deeply
sedated/Deep sleep 2 (16.7) 1 (8.3) 1 (8.3) Unarousable 0 0 0 Post
Infusion Hour 18 0.3840 Awake and alert 0 1 (8.3) 2 (16.7)
Minimally sedated/Sleepy 2 (16.7) 3 (25.0) 0 Moderately sedated/ 2
(16.7) 1 (8.3) 2 (16.7) Somnolent Deeply sedated/Deep sleep 1 (8.3)
0 0 Unarousable 0 1 (8.3) 0 Post Infusion Hour 22 0.4821 Awake and
alert 1 (8.3) 1 (8.3) 0 Minimally sedated/Sleepy 0 0 0 Moderately
sedated/ 2 (16.7) 0 1 (8.3) Somnolent Deeply sedated/Deep sleep 0 0
0 Unarousable 0 1 (8.3) 0 Post Infusion Hour 26 -- Awake and alert
0 0 0 Minimally sedated/Sleepy 1 (8.3) 0 0 Moderately sedated/ 0 0
0 Somnolent Deeply sedated/Deep sleep 0 0 0 Unarousable 0 0 0
.sup.aLow-dose dexmedetomidine: (0.35 .mu.g/kg bolus, 0.25
.mu.g/kg/hour infusion). .sup.bModemte-dose dexmedetomidine: (0.7
.mu.g/kg bolus, 0.5 .mu.g/kg/hour infusion). .sup.cHigh-dose
dexmedetomidine: (1.0 .mu.g/kg bolus, 0.75 .mu.g/kg/hour infusion).
.sup.dP-values are from Cochran-Mantel-Haenszel test. Note: Patient
33 UMSS scores were not applicable due to continuous infusion of
neuromuscular blockade. ITT = Intent-to-Treat, -- = not applicable,
N = number of patients, UMSS = University of Michigan Sedation
Scale
[0341] A summary of the level of sedation (BIS scores) at each time
point during the treatment period for the ITT Population was
reviewed. Patients became less sedated from the time of infusion to
6 hours post-infusion. This was more apparent with the low and
moderate doses of dexmedetomidine; the pre-infusion mean changes
from Baseline maximum BIS values were -1.0.+-.9.72 and
-5.8.+-.13.22 for patients in the low and moderate dose groups,
respectively. Six hours post-infusion, the mean changes from
Baseline maximum BIS values were 12.7.+-.28.52 and 14.2.+-.12.21
for patients in the low and moderate dose groups, respectively.
Patients who received the highest dose of dexmedetomidine also
became increasingly awake with time; however, the mean changes from
Baseline to up to 6 hours post-infusion were less than observed
with the lower doses; the preinfusion mean change from the Baseline
maximum BIS score was -8.2.+-.13.43, and at 6 hours post-infusion
it was 2.3.+-.14.86. The SQI at each time point during the
treatment period for the ITT Population was summarized. The SQI
values were similar among the three dexmedetomidine dose groups at
post-bolus dose/pre-infusion and remained consistently stable
through 16 hours post infusion; there was more variability after 16
hours post-infusion of dexmedetomidine.
[0342] An analysis of the correlation between the UMSS score and
dexmedetomidine plasma concentration is presented in Table 41. The
Pearson correlation was used to test zero correction of
dexmedetomidine of plasma and UMSS scores, significant correlation
was observed at the following timepoints: 30 minutes after start of
infusion of low dose-dexmedetomidine (p=0.0266), 8 hours after the
EOI of moderate dose dexmedetomidine (p=0.0423), and 30 to 15
minutes prior to the EOI (p=0.0255) and 60 minutes after the EOI
(0.0502) of high-dose dexmedetomidine. With the exception of these
time points, dexmedetomidine plasma concentrations did not
correlate with UMSS sedation scores.
TABLE-US-00043 TABLE 41 Analysis of Correlation between the
University of Michigan Sedation Scale and Dexmedetomidine Plasma
Concentration-ITT Population Low Dose.sup.a Moderate Dose.sup.b
High Dose.sup.c N-12 N = 12 N = 12 Timepoint/ Dex p- Dex p- Dex p-
Statistics Plasma UMSS value Plasma UMSS value Plasma UMSS value
Pre-dose n 12 12 12 12 11 11 Mean (SD) 0 3.8 0 3.9 0 3.9 (0.87)
(0.29) (0.30) Median 0 4.0 0 4.0 0 4.0 (Min, Max) (1, 4) (3, 4) (3,
4) End of bolus n 12 12 0 0 0 0 Mean (SD) 269.7 3.7 0.1517 N/A N/A
-- N/A N/A -- (127.08) (0.89) Median 208.0 4.0 N/A N/A N/A N/A
(Min, Max) (106. 473) (1, 4) 30 min after start of infusion n 12 12
11 11 11 11 Mean (SD) 120.4 3.5 0.0266 250.5 3.5 0.1935 390.9 3.8
0.4164 (31.76) (1.00) (76.56) (0.69) (185.66) (0.60) Median 125.5
4.0 238.0 4.0 339.0 4.0 (Min, Max) (39, 155) (1, 4) (161, 413) (2,
4) (146, 765) (2, 4) 60 min after start of infusion n 0 0 8 8 8 8
Mean (SD) N/A N/A -- 336.3 3.8 0.8044 424.4 3.4 0.9112 (186.45)
(0.46) (147.62) (0.92) Median N/A N/A 317.0 4.0 463.0 4.0 (Min,
Max) (115, 711) (3, 4) (138, 578) (2, 4) 2 hours after start of
infusion n 0 0 11 11 11 11 Mean (SD) N/A N/A -- 326.1 3.4 0.4939
560.6 3.2 0.5981 (127.04) (0.81) (119.26) (0.87) Median N/A N/A 300
4.0 586.0 3.0 (Min, Max) (159, 620) (2, 4) (281, 702) (2, 4) 4 to 6
hours after start of infusion n 0 0 11 11 10 10 Mean (SD) N/A N/A
-- 413.4 1.6 0.2884 592.9 2.4 0.9560 (222.55) (1.03) (82.56) (0.84)
Median N/A N/A 367.0 2.0 613 2.0 (Min, Max) (112, 1010) (0, 3)
(393, 689) (1, 4) 6 hours after start of infusion n 7 7 0 0 0 0
Mean (SD) 230.0 2.3 0.1466 N/A N/A -- N/A N/A -- (111.54) (1.25)
Median 187.0 2.0 N/A N/A N/A N/A (Min, Max) (113, 428) (0, 4) 12
hours after start of infusion n 2 2 0 0 0 0 Mean (SD) 299.0 2.0 --
N/A N/A -- N/A N/A -- (165.46) (0.00) Median 299.0 2.0 N/A N/A N/A
N/A (Min, Max) (182, 416) (2, 2) 30-15 min prior to end of infusion
n 0 0 11 11 9 9 Mean (SD) N/A N/A -- 423.6 1.6 0.5137 801.3 2.3
0.0255 (164.14) (1.03) (281.08) (0.50) Median N/A N/A 394.0 2.0
686.0 2.0 (Min, Max) (307, 890) (0, 4) (504, 1340) (2, 3) End of
infusion n 12 12 0 0 0 0 Mean (SD) 220.5 1.5 0.3485 N/A N/A -- N/A
N/A -- (98.04) (1.09) Median 205.5 2.0 N/A N/A N/A N/A (Min, Max)
(77, 420) (0, 3) 15 min after end of infusion n 1 1 9 9 7 7 Mean
(SD) 272.0 3.0 -- 423.3 1.7 0.3181 758.0 2.6 0.3601 (N/A) (N/A)
(194.88) (1.12) (282.80) (0.98) Median 272.0 3.0 383.0 1.0 680.0
3.0 (Min, Max) (272, 272) (3, 3) (254, 925) (0, 3) (493, 1280) (1,
4) 30 minutes after end of infusion n 6 6 2 2 1 1 Mean (SD) 192.7
2.3 0.8999 318.5 2.5 -- 447.0 2.0 -- (93.68) (1.03) (30.41) (0.71)
(N/A) (N/A) Median 171.0 2.0 318.5 2.5 447.0 2.0 (Min, Max) (84,
347) (1, 4) (297, 340) (2, 3) (447, 447) (2, 2) 60 min after end of
infusion n 6 6 10 10 9 9 Mean (SD) 99.2 0.8 0.1082 310.9 1.7 0.2190
504.4 1.6 0.0502 (68.05) (0.75) (107.54) (1.16) (271.32) (1.24)
Median 85.5 1.0 285.0 1.5 431.0 2.0 (Min, Max) (37, 216) (0, 2)
(189, 582) (0, 4) (115, 1080) (0, 3) 2 hours after end of infusion
n 11 11 10 10 10 10 Mean (SD) 84.3 1.8 0.8720 188.4 1.1 0.8269
351.6 1.3 0.3666 (59.49) (0.75) (67.88) (0.88) (179.77) (1.6)
Median 60.0 2.0 174.5 1.0 268.5 1.0 (Min, Max) (31, 207) (1, 3)
(88, 332) (0, 2) (213, 772) (0, 3) 4 hours after end of infusion n
7 7 9 9 7 7 Mean (SD) 50.7 1.1 0.5451 93.8 0.8 0.6763 185.3 1.3
0.1680 (36.09) (0.90) (61.29) (1.30) (131.80) (1.11) Median 45.0
1.0 72.0 0.0 116.0 1.0 (Min, Max) (8, 96) (0, 2) (28, 232) (0, 4)
(45, 411) (0, 3) 8 hours after end of infusion n 6 6 4 4 7 7 Mean
(SD) 13.2 1.2 0.5885 12.4 1.0 0.0423 51.2 0.4 0.4667 (15.04) (0.98)
(12.45) (0.82) (51.88) (0.79) Median 10.0 1.5 10.3 1.0 19.5 0.0
(Min, Max) (0, 39) (0, 2) (0, 29) (0, 2) (10, 143) (0, 2) 12 Hours
after end of infusion n 2 2 2 2 2 2 Mean (SD) 10.0 1.0 -- 4.2 1.0
-- 36.0 1.5 -- (14.14) (1.41) (5.99) (0.00) (26.87) (0.71) Median
10.0 1.0 4.2 1.0 36.0 1.5 (Min, Max) (0, 20) (0, 2) (0, 8) (1, 1)
(17, 55) (1, 2) 15 to 18 hours after end of infusion n 0 0 1 l 0 0
Mean (SD) N/A N/A -- 0 0 -- N/A N/A -- (N/A) (N/A) Median N/A N/A
0.0 0.0 N/A N/A (Min, Max) (0, 0) (0, 0) Note: Correlation p-values
(Pearson product moment) assessed within treatment groups.
.sup.aLow-dose dexmedetomidine (0.35 .mu.g/kg bolus, 0.25
.mu.g/kg/hour infusion). .sup.bModerate-dose dexmedetomidine (0.7
.mu.g/kg bolus, 0.5 .mu.g/kg/hour infusion). .sup.cHigh-dose
dexmedetomidine (1.0 .mu.g/kg bolus, 0.75 .mu.g/kg/hour infusion).
DEX = dexmedetomidine, ITT = Intent-to-Treat, max = maximum, min =
minimum, N, n = number of patients, SD = standard deviation, UMSS =
University of Michigan sedation scale
[0343] An analysis of the correlation between UMSS scores and
dexmedetomidine plasma AUC.sub.0-t was conducted. The data
presentation was not clinically meaningful.
[0344] An analysis of the correlation between the UMSS scores and
Cl.sub.w of dexmedetomidine from plasma was conducted. The
strongest correlation was observed for the low dose; significant
correlations were observed at pre-infusion (p=0.0015), 1 hour
post-infusion (p=0.0191), and 12 hours post-infusion (p=0.0385). A
significant correlation was also observed for the high dose of
dexmedetomidine at the time infusion was discontinued (p=0.0295).
An analysis of the correlation between the UMSS scores and Cl of
dexmedetomidine was conducted. Significant correlation between UMSS
scores and clearance of dexmedetomidine was observed for low-dose
dexmedetomidine at pre-infusion and 12 hours post-infusion
(p=0.0371 and p=0.0470, respectively).
[0345] Only patients with sufficient pharmacokinetic data to
calculate the primary pharmacokinetic parameters were included in
the pharmacokinetic analysis population. In general, missing data
were not imputed.
[0346] Pharmacokinetic sample collection times and the respective
observed values for dexmedetomidine were reviewed by patient for
patients that received the low dose-dexmedetomidine (0.25
.mu.g/kg/hour), for patients that received the moderate-dose
dexmedetomidine (0.5 .mu.g/kg/hour), and for patients that received
the high-dose dexmedetomidine (0.75 .mu.g/kg/hour). Pharmacokinetic
parameters reviewed as natural log transformed values for
dexmedetomidine. Pharmacokinetic parameters displayed as observed
values for dexmedetomidine were also reviewed.
[0347] An analysis of the correlation between the UMSS score and
dexmedetomidine plasma concentration is presented in Table 41.
There was no data presenting relationship to response. A
significant correlation for UMSS score and dexmedetomidine plasma
concentration was observed at the following timepoints: 30 minutes
after start of infusion of low-dose dexmedetomidine (p=0.0266), 30
to 15 minutes prior to the end of infusion of high-dose
dexmedetomidine (p=0.0255), and 8 hours after the end of infusion
of moderate-dose dexmedetomidine (p=0.0423).
[0348] The pharmacokinetic profile demonstrated linearity and dose
proportionality among 0.25, 0.50 and 0.75 .mu.g/kg/hour dose
levels; as dose increased, AUC and C.sub.max increased in
proportion. The mean doses were given as 20.5, 40.4, and 65.1 .mu.s
to 0.25, 0.50 and 0.75 .mu.g/kg/hour dose levels, respectively; as
shown dose increased accordingly. AUC.sub.0-inf and C.sub.max of
dexmedetomidine were dose-proportional at the 0.25 to 0.75
.mu.g/kg/hour dose level. The apparent t.sub.1/2 of dexmedetomidine
was 2.33 hrs, 2.12 hrs, and 3.05 hrs for the low, moderate, and
high dose levels, respectively. The geometric mean slope among the
three dose levels and 95% confidence intervals were 1.263 (0.820,
1.706) for AUC.sub.0-inf, and 0.898 (0.652, 1.143) for C.sub.max. A
dose-dependent increase in mean plasma concentration, AUC.sub.0-t,
and AUC.sub.0-inf was observed between the three dexmedetomidine
dose groups. Dose proportionality was concluded for AUC.sub.0-t,
AUC.sub.0-inf, and C.sub.max for dexmedetomidine in this study. No
notable differences in weight-adjusted clearance versus age were
observed for any dose groups.
[0349] Patients had deep sedation (UMSS 3-4) from pre-dose to 2
hours after infusion, and maintained a moderate level of sedation
(UMSS 1-3) after 4 hours infusion through the end of infusion for
all dose levels. There was a correlated relationship between plasma
concentration and UMSS for low dose 30 minutes after start of
infusion, moderate dose 8 hours after end of infusion, and high
dose 30-15 minutes prior to end of infusion and 60 minutes after
end of infusion.
[0350] Thirty-eight patients received at least one dose of
dexmedetomidine and were included in the safety analysis set. Two
patients (assigned to the high-dose dexmedetomidine treatment
group) did not complete the study treatment; these patients were
not included in the ITT or pharmacokinetic analysis. Twelve
patients within each treatment group (36 patients total) completed
study drug infusion. Exposure to study drug is summarized in Table
42. The mean doses given to the 36 ITT patients were 20.5, 40.4,
and 65.1 .mu.g for the 0.25, 0.50 and 0.75 .mu.g/kg/hour dose
levels, respectively as shown dose increased accordingly. The mean
duration of dose infused was approximately 9.1, 10.0, and 11.2
hours for low, moderate, and high dose levels, respectively.
TABLE-US-00044 TABLE 42 Summary of Exposure to Dexmedetomidine
(Total Dose)-ITT Population Low Dose.sup.a Moderate Dose.sup.b High
Dose.sup.c N = 12 N = 12 N = 12 Total dose (.mu.g).sup.d Mean (SD)
20.5 (14.92) 40.4 (18.32) 65.1 (28.91) Median 16.6 (10, 65) 39.0
(15, 73) 53.9 (35, 124) (Min, Max) Duration of Dose (min).sup.e
Mean (SD) 544.8 (362.89) 601.3 (363.96) 669.0 (396.82) Median 407.5
(260, 1434) 526.5 (187, 1441) 533.0 (264, 1369) (Min, Max)
.sup.aLow-dose dexmedetomidine: (0.35 .mu.g/kg bolus, 0.25
.mu.g/kg/hour infusion). .sup.bModerate-dose dexmedetomidine: (0.7
.mu.g/kg bolus, 0.5 .mu.g/kg/hour infusion). .sup.cHigh-dose
dexmedetomidine: (1.0 .mu.g/kg bolus, 0.75 .mu.g/kg/hour infusion).
.sup.dTotal dose equals the sum of loading and maintenance doses.
.sup.eDuration of total dose is the sum of loading and maintenance
dose duration. ITT = Intent-to-Treat, max = maximum, min = minimum,
N = number of patients, SD = standard deviation
[0351] All 38 patients in the safety population and 36 ITT patients
experienced at least 1 treatment-emergent adverse effect during the
time that the first dose of dexmedetomidine was administered until
24 hours had elapsed following discontinuation of study drug
administration. Thirty-three patients experienced
treatment-emergent adverse effects considered to be
treatment-related. The SOCs with the highest incidence of
treatment-emergent adverse effects included the vascular disorders
SOC (10 patients [83.3%] while receiving the low dose of
dexmedetomidine, 10 patients [83.3%] while receiving the moderate
dose of dexmedetomidine, and 14 patients [100.0%] during treatment
with the high dose of dexmedetomidine) and the metabolism and
nutrition disorders SOC (10 patients [83.3%] while receiving the
low dose of dexmedetomidine, 12 patients [100.0%] while receiving
the moderate dose of dexmedetomidine, and 7 patients [50.0%] while
receiving the high dose of dexmedetomidine); and cardiac disorders
SOC (3 patients [25.0%] during treatment with the low dose of
dexmedetomidine, 4 patients [33.3%] during treatment with the
moderate dose of dexmedetomidine, and 4 patients [28.6%] during
treatment with the high dose of dexmedetomidine).
[0352] The majority of Treatment-emergent adverse effects were
considered mild in intensity (9 patients [75.0%] for the low dose
of dexmedetomidine, 9 patients [75.0%] for the moderate dose of
dexmedetomidine, and 7 patients [50.0%] for the high dose of
dexmedetomidine). A small percentage of Treatment-emergent adverse
effects was considered moderate in intensity (2 patients [16.7%]
for the low dose of dexmedetomidine, 3 patients [25.0%] for the
moderate dose of dexmedetomidine, and 7 patients [50.0%] for the
high dose of dexmedetomidine). One patient in the low-dose
dexmedetomidine treatment group experienced a Treatment-emergent
adverse effect that was considered severe. The majority of
Treatment-emergent adverse effects were considered drug-related:
low-dose dexmedetomidine (11 patients, 91.7%); moderate-dose
dexmedetomidine (11 patients, 91.7%); and high-dose dexmedetomidine
(11 patients, 78.6%).
[0353] One hundred and seventy-one (171) treatment-emergent adverse
effects were reported by 38 patients in the Safety Population. Four
patients, 3 in the high dose group and 1 in the moderate dose group
experienced a treatment-emergent adverse effect leading to
discontinuation of study drug. No patients discontinued study drug
as a result of death. The most commonly reported treatment-emergent
adverse effects were hyperglycemia and hypertension. The incidence
of hyperglycemia was higher with the moderate dose of
dexmedetomidine compared with the low dose and high dose of
dexmedetomidine (low-dose dexmedetomidine, 83.3%; moderate-dose
dexmedetomidine, 100.0%; high-dose dexmedetomidine, 50.0%). The
incidence of hypertension was similar across all three dose groups
of dexmedetomidine (low-dose dexmedetomidine, 66.7%; moderate-dose
dexmedetomidine, 58.3%; high-dose dexmedetomidine, 71.4%).
[0354] Study drug-related treatment-emergent adverse effect of
hypertension occurred with the highest incidence (low-dose
dexmedetomidine, 66.7%; moderate-dose dexmedetomidine, 58.3%;
high-dose dexmedetomidine, 50.0%). The incidence of drug-related
treatment-emergent adverse effects was similar across all three
dose groups of dexmedetomidine. The majority of treatment-emergent
adverse effects experienced by patients in the low and moderate
dexmedetomidine dose groups were mild in intensity (low dose, 9
patients, 75.0%; moderate dose, 9 patients, 75.0%).
[0355] A smaller percentage of patients experienced
treatment-emergent adverse effects that were moderate in intensity
in the low and moderate dexmedetomidine dose groups (low dose, 2
patients, 16.7%; moderate dose, 3 patients, 25.0%). A similar
percentage of patients experienced both mild and moderate
treatment-emergent adverse effects in the high dexmedetomidine
treatment group; 7 patients, 50.0% experienced mild
treatment-emergent adverse effects and 7 patients, 50.0%
experienced moderate treatment-emergent adverse effects. Only one
severe treatment-emergent adverse effect was reported and that was
in the low dexmedetomidine dose group.
[0356] Twenty-five patients experienced at least one
treatment-emergent adverse effect considered by the investigator to
be mild during the study. Twelve patients experienced at least one
treatment-emergent adverse effect considered to be moderate, and 1
patient experienced at least one treatment-emergent adverse effect
considered to be severe in intensity. One death was reported during
the study. Four patients experienced treatment-emergent adverse
effects that led to discontinuation of study drug.
[0357] There were no meaningful differences in clinical laboratory
test results, select vital signs (systolic blood pressure,
diastolic blood pressure, mean arterial blood pressure, body
temperature, respiratory rate), or physical examination findings
between the three dexmedetomidine dose levels. Clinically
significant hematology abnormalities were observed for 1 patient
(8.3%) each in the low and moderate-dose dexmedetomidine groups
(anemia) and two patients (16.7%) in the low-dose dexmedetomidine
group (thrombocytopenia). With the exception of one patient in the
low-dose dexmedetomidine group that had thrombocytopenia, none of
these reported adverse effects were treatment-emergent. Greater
mean change in heart rate was observed for patients in the
high-dose dexmedetomidine treatment group compared to the other
treatment groups at all time points.
[0358] The following clinically significant abnormalities in
chemistry laboratory data considered as adverse events were
observed: hyperkalemia (one patient in each dose group),
hypernatremia (one patient in the low dose group), hypocalcemia
(one patient in each low and moderate dose group), hypoglycemia
(one patient each in the low and moderate dose groups), and
hypokalemia (one patient each in the low and moderate dose
groups).
[0359] Treatment-emergent adverse effects associated with vascular
disorders included hypertension (8 patients, low dose; 7 patients,
moderate dose; and 10 patients, high dose) and hypotension (5
patients, low dose; 5 patients, moderate dose; and 10 patients,
high dose). A statistically significant treatment difference for
change from Baseline for heart rate, up to and including Post
Infusion Hour 5, was observed. Treatment-emergent adverse effects
associated with heart rate included tachycardia in 3 patients
administered low-dose dexmedetomidine, 1 patient administered
moderate-dose dexmedetomidine, and 3 patients administered
high-dose dexmedetomidine. A statistically significant treatment
difference for change from Baseline in temperature was observed
Post Infusion Hour 28; temperature change from Baseline was
-1.43.+-.1.559.degree. C., 0.30.+-.0.265.degree. C., and
1.46.+-.1.041.degree. C. for the low, moderate, and high dose of
dexmedetomidine, respectively (p=0.008); no significant differences
were observed at any other time point. Treatment-emergent adverse
effects associated with body temperature included hypothermia (1
patient, low dose and 2 patients, moderate dose), and hyperthermia
(1 patient, low dose and 1 patient, high dose). No clinically
meaningful changes in respiratory rate were observed and no related
adverse effects were reported. No physical examination findings
were considered clinically significant or were reported as adverse
effects. ECG results were reported as adverse effects for 7
patients. ECG-related adverse effects included ischemia (2 patients
both in the low dose group), ECG inverted T-wave (1 patient in the
low dose group), elevated ST segment (1 patient in the low dose
group), bradycardia (1 patient in the moderate dose group), ECG
change (1 patient in the high dose group), and sinus bradycardia
complete heart block (1 patient in the high dose group).
[0360] Hepatotoxicity, as defined in the SAP, was reported in 1
patient (8.3%) in the low dose group (within 24 hours of
discontinuation of infusion), 1 patient (8.3%) in the moderate dose
group (2 to 4 weeks post-infusion or at the next follow-up visit),
and 2 patients (14.3%) in the high dose group (within 24 hours of
discontinuation of infusion); no adverse effects related to
hepatotoxicity were reported. No patients reported DLT in this
study.
[0361] Fentanyl was administered as an additional intra-operative
sedation agent to patients in each dexmedetomidine dose level. The
amount of fentanyl administered was lower in patients receiving
moderate (69.32 .mu.g), and high (80.20 .mu.g) doses of
dexmedetomidine compared to those receiving low (99.32 .mu.g)
levels. Post-operatively, patients were administered fentanyl,
midazolam, and morphine sulfate. There was no treatment difference
observed related to the quantity of additional sedation received
for any of the additional sedation agents. At most time points
observed post-infusion, there was an increase in the percentage of
patients who were administered additional sedation or analgesia for
patients that received moderate levels of dexmedetomidine compared
to those who received low levels. For most time points
post-infusion, there was a decrease in the percentage of patients
that received additional sedation or analgesia in the
dexmedetomidine high dose level compared to those in the low dose
level. There was no clear relationship between dexmedetomidine dose
level and the quantity of fentanyl, midazolam, and morphine sulfate
administered to patients at any post-infusion time point
observed.
[0362] This was a single center, phase I dose escalation
pharmacokinetic, pharmacodynamic study of a single bolus dose of
dexmedetomidine followed by a continuous infusion for up to 24
hours in infants who were immediately post-operative from cardiac
surgery and required tracheal intubation with mechanical
ventilation in the post-operative period. Dexmedetomidine is a
highly selective alpha2 agonist with hypnotic and anxiolytic
properties attributed to the alpha2A-adrenoreceptors in the locus
ceruleus. Dexmedetomidine was initially approved in 1999 for the
sedation of intubated and mechanically ventilated patients in the
intensive care setting for up to 24 hours, and dexmedetomidine was
recently approved as a short term (<24 hours) sedative
medication for use in adult non-intubated patients requiring
sedation prior to and during surgical and other procedures.
Thirty-eight infants, status post-cardiac surgery, were assigned to
three treatment groups: low-dose dexmedetomidine (12 patients),
moderate-dose dexmedetomidine (12 patients), and high-dose
dexmedetomidine (14 patients). Thirty-six patients, 12 in each dose
group, completed the dexmedetomidine infusion. Patients were
predominantly Caucasian (61.1%) with a mean age of 8.3 months.
Patients in the low-dose dexmedetomidine group received 0.35
.mu.g/kg bolus, 0.25 .mu.g/kg/hour infusion, patients in the
moderate-dose dexmedetomidine group received 0.7 .mu.g/kg bolus,
0.5 .mu.g/kg/hour infusion, and patients in the high-dose
dexmedetomidine group received 1 .mu.g/kg bolus, 0.75 .mu.g/kg/hour
infusion. Pharmacokinetic samples were collected prior to the bolus
dose through up to 18 hours after the EOI time points for
measurement of dexmedetomidine pharmacokinetic parameters. There
were 36 patients in the Pharmacokinetic Population; 36 patients
completed treatment. Sedation and analgesic properties of the drug
were to be assessed by a periodic check of the BIS monitor until
after infusion was discontinued and the patient was deemed awake by
the clinical care team. The UMSS score was also assessed on an
hourly basis until the BIS sensor was removed.
[0363] The primary variables for pharmacokinetic assessment of
dexmedetomidine were observed peak plasma concentration
(C.sub.max), area under the plasma concentration-time curve from
time zero to the last quantifiable timepoint (AUC.sub.0-t), area
under the plasma concentration-time curve from time zero to
infinity (AUC.sub.0-inf), time of observed peak plasma
concentration (T.sub.max), terminal elimination rate constant
(.lamda.z), terminal half-life (t.sub.1/2), end of infusion
concentration (steady state C.sub.ss), plasma clearance (Cl), and
volume of distribution (V.sub.d). Dose-proportionality was
demonstrated with the analysis of mean values of C.sub.max,
AUC.sub.0-t, and AUC.sub.0-inf. There was no apparent change in
clearance and weight-adjusted clearance across the age range in
this study. Pharmacodynamic assessments were monitored continuously
every hour until 24 hours after the discontinuation of the infusion
and included heart rate, blood pressure, mean arterial blood
pressure, cardiac rhythm, oxygen saturation, and respiratory rate.
The BIS and the UMSS were used to assess the level of sedation.
There were no meaningful differences in systolic blood pressure,
diastolic blood pressure, mean arterial blood pressure, body
temperature, respiratory rate), or physical examination findings
between the 3 dexmedetomidine dose levels. Administration of a
higher bolus dose resulted in a deeper level of sedation (BIS); the
change from Baseline was less for patients that received the high
dose of dexmedetomidine than the lower doses up to 6 hours
post-infusion. Of the 38 patients in the Safety Population, all
patients experienced at least 1 adverse effect that was considered
treatment-emergent. Thirty-three patients experienced at least one
adverse effect that was considered to be treatment-related. The
SOCs with the highest incidence of treatment-emergent adverse
effects included the vascular disorders SOC (10 patients [83.3%]
while receiving the low dose of dexmedetomidine, 10 patients
[83.3%] while receiving the moderated dose of dexmedetomidine, and
14 patients [100.0%] during treatment with the high dose of
dexmedetomidine) and the metabolism and nutrition disorders SOC (10
patients [83.3%] while receiving the low dose of dexmedetomidine,
12 patients [100.0%] while receiving the moderate dose of
dexmedetomidine, and 7 patients [50.0%] while receiving the high
dose of dexmedetomidine). In this study, no patients experienced a
DLT.
[0364] In alignment with the primary objectives of this study,
dose-dependent increases in pharmacokinetic (mean plasma
concentration, AUC.sub.0-t, and AUC.sub.0-inf) and level of
sedation were demonstrated in this study. At most time points
investigated, no significant correlation between the level of
sedation and serum plasma concentration, AUC.sub.0-t, or
AUC.sub.0-inf was observed for any doses tested. In addition, no
correlation between UMSS scores and clearance of dexmedetomidine
(weight adjusted and non-weight-adjusted) was observed at the
majority of time points tested. Dexmedetomidine was generally well
tolerated in infant postoperative cardiac patients.
[0365] The following conclusions were derived regarding the
administration of dexmedetomidine for infants post-operative from
cardiac surgery:
[0366] The pharmacokinetic profile demonstrated linearity and dose
proportionality among 0.25, 0.50 and 0.75 .mu.g/kg/hour dose
levels; as dose increased, AUC and C.sub.max increased in
proportion.
[0367] Patients had deep sedation (UMSS 3-4) from pre-dose to 2
hours after infusion, and maintained a moderate level of sedation
(UMSS 1-3) after 4 hours infusion through the end of infusion for
all dose levels.
[0368] There was a correlated relationship between plasma
concentration and UMSS for low dose 30 minutes after start of
infusion, moderate dose 8 hours after end of infusion, and high
dose 30-15 minutes prior to end of infusion and 60 minutes after
end of infusion.
[0369] There was no apparent change in clearance or weight-adjusted
clearance across the age range studied in this study.
[0370] At the majority of time points, there was no correlation
observed between serum plasma concentration of dexmedetomidine and
the level of sedation or clearance of dexmedetomidine.
[0371] Greater mean change in heart rate was observed for patients
in the high-dose dexmedetomidine treatment group compared to the
other treatment groups.
[0372] The doses of dexmedetomidine administered in this study were
generally well tolerated.
[0373] No clinically meaningful differences in the safety profile
were observed between the three dose groups.
Example 6: Pooled Pharmacokinetic Data of Dexmedetomidine in
Pediatric Patients
[0374] The pharmacokinetic data from the Example 1 study, the
Example 3 study, and the Example 5 study were pooled. Data was
included for patients who received treatment with dexmedetomidine
and had at least 1 measurable plasma concentration with the
associated dosing and sample timing information. For Example 1, the
only subjects included were in the original 30 patient population
study. For Example 5, data was only included from patients who had
received at least 2 hours of a maintenance infusion of
dexmedetomidine and who had at least one measurable plasma
concentration with the associated dosing and sample timing
information. A population pharmacokinetics analysis of
dexmedetomidine, including covariate assessment, was performed on
the data.
[0375] Full-profile pharmacokinetics sampling was performed in all
subjects in the Example 5 and Example 3 studies. In the Example 1
study, blood was collected at 6 or 7 protocol-designated times for
subjects based on subject age and weight. In the Example 1 study,
blood samples (0.15 mL) for pharmacokinetics analysis were
collected via a central or peripheral venous or arterial line
unless access was unavailable, in which case samples were collected
from a capillary draw (heel stick). Where appropriate, blood
samples were drawn at a site opposite from the site of infusion.
Subjects in Group I who weighed less than 2 kg had blood drawn at
the end of the loading dose, 10 to 14 h after the start of the
maintenance infusion, at the end of the maintenance infusion, 10 to
30 minutes post-maintenance, and 3 to 4 h and 6 to 10 h
post-maintenance. Subjects in Group I who weighed at least 2 kg had
blood drawn at the end of the loading dose, 4 to 8 h and 10 to 14 h
after the start of the maintenance infusion, at the end of the
maintenance infusion, and 10 to 30 minutes post-maintenance, and 1
to 2 h and 6 to 10 h post-maintenance. Subjects in Group II had
blood drawn at the end of the loading dose, 4 to 8 h after the
start of the maintenance infusion, at the end of the maintenance
infusion, 10 to 30 minutes post-maintenance, and 1 to 2 h, 3 to 4
h, and 6 to 10 hrs post-maintenance.
[0376] In the Example 5 study, blood samples (1 mL) for
pharmacokinetics measurements were drawn at a site distant from the
infusion. Blood was drawn according to the following schedule:
prior to the loading dose, 0.5, 1, 2, 4 to 6 hrs after the start of
the maintenance infusion, 30 to 15 minutes prior to end of the
maintenance infusion, and 0.25, 0.5, 1, 2, 4, 8, 12, and 15 to 18
hrs after the end of the maintenance infusion.
[0377] In Study Example 3, venous blood samples (1 mL) for
pharmacokinetics measurements were collected at a site opposite
from the site of infusion. Blood was drawn according to the
following schedule: .ltoreq.30 minutes prior to the loading dose,
within 5 minutes before the end of the loading dose, 0.5, 1, 2, 4
to 6 h after the start of the maintenance infusion, within 30
minutes prior to the end of the maintenance infusion, and 10
minutes, 0.5, 1, 2, 4, and 10 hrs after the end of the maintenance
infusion.
[0378] Blood samples were collected into labeled tubes containing
heparin as anticoagulant. A validated high-performance liquid
chromatography-tandem mass spectrometry method for quantitation of
dexmedetomidine in human plasma was used. The lower limit of
quantitation (LLOQ) was 4.24 pg/mL for the Example 5 study, 30.24
pg/mL for Study Example 3, and 29.97 pg/mL for the Example 1 study.
For Study Example 3 and the Example 1 study, dosing information,
pharmacokinetics sampling information, dexmedetomidine
concentrations, and covariate data were merged, as necessary, to
construct a time-ordered sequence of relevant events for each
subject from the start time of the first dose until the time of
last blood sample in analysis-ready datasets. Analysis-ready
datasets for Study Example 3 and the Example 1 study were set
together with the supplemented analysis-ready dataset for the
Example 5 study.
[0379] The potential of selected covariates to explain variability
in the pharmacokinetics parameters for dexmedetomidine was
explored. The following time-invariant (stationary) demographic and
clinical covariates were determined at the screening visit and were
assumed to remain constant for the duration of the trial: [0380]
Body weight, kg [0381] Age, years [0382] Alanine aminotransferase,
U/L [0383] Total bilirubin, mg/dL [0384] Ethnicity: 1=Caucasian,
2=Black, 3=Asian, 4=Native American, 5=Hispanic, 6=other [0385]
Sex: 0=male, 1=female [0386] Heart physiology: 0=double-ventricle,
1=single-ventricle [0387] Use of concomitant glucuronidation
pathway inhibitors 24 h prior to or during surgery or during the
treatment period: 0=no, 1=yes [0388] Intravenous albumin infusion:
0=no, 1=yes [0389] Cardio-pulmonary bypass use: 0=no, 1=yes [0390]
Gestational age: 1=preterm (.gtoreq.28 through .ltoreq.36 weeks),
0=term (.gtoreq.36 through .ltoreq.44 weeks) and [0391] Site of
sampling, 0=venous, 1=arterial, 2=capillary (heel stick).
[0392] Site of sampling was recorded only in the Example 1 study
and was assumed to be venous for the studies where no information
was recorded. The effect of concomitant metabolic inducers could
not be explored due to the limited timeframe for the past
medication history collection as specified in the Example 5 study
(that is, 24 h prior to surgery). Aspartate aminotransferase and
serum albumin data were not available from the Example 5 study and
were, therefore, not considered as possible covariates.
[0393] Although dexmedetomidine is a substrate of CYP2A6,
comprehensive literature review regarding inhibition of CYP2A6
identified a very limited number of commercially available drugs
shown to inhibit this CYP enzyme. When the likelihood of use of
these agents in a pediatric population was considered, further
covariate evaluation of this factor was determined to be
unnecessary.
[0394] SAS Version 9.1 or later was used for data preparation,
summary statistics, and graphical displays. Summary statistics were
computed to describe dependent and independent variables, including
mean, median, standard deviation, and other measures, as
appropriate. Population pharmacokinetic modeling was performed
using the computer program NONMEM.RTM., Version VI, Level 2.0.
NONMEM analyses were performed on Intel x86 computers running the
OpenSUSE 10.2 distribution of Linux. The Fortran compiler used was
the GNU Fortran compiler, part of the GCC Version 3.3.5
compiler.
[0395] For each analysis, NONMEM computes the minimum value of the
objective function (MVOF), a statistic that is proportional to
minus twice the log likelihood of the data. In the case of
hierarchical models, the change in the MVOF produced by the
inclusion of a parameter is asymptotically .chi.2-distributed with
the number of degrees of freedom equal to the number of parameters
added to or deleted from the model. The first-order conditional
estimation (FOCE) with interaction method was used at all stages of
the model development process.
[0396] A variety of graphs and tables were generated from the
analysis dataset to understand the informational content of the
data with respect to the anticipated model, to search for extreme
values and/or potential outliers, to assess possible trends in the
data, and to determine if any errors were made in the manipulation
of the data and creation of the analysis dataset. This exploratory
analysis was also used to confirm the appropriateness of the models
to be tested and to verify model assumptions. Data visualization
techniques were used to search for patterns and extreme values that
may have caused significant bias during the analysis. An outlier
was defined as an aberrant observation that significantly deviated
from the rest of the observations measured in a particular subject.
The general procedure that was followed for the development of the
pharmacokinetics model of dexmedetomidine is outlined below.
[0397] 1. Exploratory data analysis.
[0398] 2. Refinement of the dexmedetomidine population
pharmacokinetics model originally developed by Example 5 using the
pooled Example 5 study data and Study Example 3 data, including
covariate analysis.
[0399] 3. Further refinement of the dexmedetomidine population
pharmacokinetics model after data from the Example 1 study became
available and was pooled with the previous dataset. The influence
of covariates on the pharmacokinetics parameters was
re-evaluated.
[0400] 4. Final model evaluation using prediction-corrected visual
predictive check (VPC) procedure. To avoid potential
multicollinearity or confounding of effects in covariate submodels,
the correlations between covariates were examined. Pairwise
scatterplots of all continuous covariates and boxplots of
continuous covariates versus categorical covariates were generated.
With the exception of body weight and age, which were expected to
be correlated in this population, in no case were 2 highly
correlated covariates included in the same parameter-covariate
model.
[0401] A linear, open, 2-compartment model for dexmedetomidine was
tested initially as a potential base structural model. This model
was refined based on the dexmedetomidine concentration data from
the Example 5 and Example 3 studies in order to determine
appropriate characterization of the random effects. While this
model included effects of body weight, age, time on CPB, and
cardiac physiology (single or double ventricle) on disposition
parameters, the base structural model initially evaluated for this
analysis did not include covariate effects unless such effects were
required to achieve model stability. It was assumed that the
effects of weight and age would be considered part of the base
structural model given the characteristics of this patient
population and their likely impact on pharmacokinetics. When the
data from the Example 1 study became available, the population
pharmacokinetics model was applied to the pooled dataset and again
refined. The influence of covariates on the pharmacokinetics
parameters was re-evaluated.
[0402] Covariate analyses were performed to explore measurable
sources of dexmedetomidine variability in pharmacokinetics model
parameters with estimated interindividual variability (IIV). Table
43 lists the parameters for which the covariate effects were
considered.
TABLE-US-00045 TABLE 43 Covariates Evaluated for Relationships With
Dexmedetomidine Clearance and/or Volume of the Central Compartment
Parameter Covariate CL Vc Body weight + + Age + + Alanine
aminotransferase + Bilirubin + Ethnicity + + Sex + + Heart
physiology + Glucuronidation enzyme inhibitors + Albumin infusion +
+ Site of sampling + + Cardiopulmonary bypass + + Abbreviations:
CL, elimination clearance; Vc, volume of the central
compartment.
[0403] Graphical and statistical approaches were used to develop
the covariate models and to assess the mathematical forms of their
relationships and their statistical significance. Following the
development of the base structural pharmacokinetics model, the
influence of covariates on selected pharmacokinetics parameters for
dexmedetomidine was evaluated univariately. Diagnostic plots
illustrating the relationships between the unexplained IIV in CL
and Vc and covariates were examined to identify possible trends, as
well as the appropriate functional form (for example, linear,
power, or exponential) to be tested for the parameter-covariate
relationship. Covariates contributing at least a 3.84 change in the
MVOF (a=0.05, 1 degree of freedom for .chi.2-distribution) and a 5%
reduction in IIV in the parameter of interest were included in the
model and the process was repeated. The error models for IIV in the
full multivariable model were re-evaluated following completion of
forward selection.
[0404] Univariate backward elimination proceeded after all
adjustments had been made to the error models. A covariate was
considered significant and kept in the model if it contributed at
least a 10.83 change in the MVOF (a=0.001, 1 degree of freedom for
.chi.2-distribution) when removed from the model. The reduced
multivariable model, with all significant covariates, was evaluated
for any remaining biases in the IIV and residual variability (RV)
error models. Diagnostic plots of the unexplained IIV in the
parameters versus all covariates were evaluated to detect any
inadequacies or biases in the covariate models and to assure no
trends remain that may indicate a potential relationship had not
been sufficiently described by the model. The model was checked for
possible simplifications of covariate equations, such as power
functions that can be reduced to linear functions (power term
approximately 1.0) or significant discrete group covariates that
could be redefined using fewer groups or parameters.
Goodness-of-fit diagnostic plots were examined for model
misfit.
[0405] The adequacy of the final model was evaluated using a
simulation-based prediction corrected VPC method. The final model
was used to simulate 1000 replicates of the analysis dataset with
NONMEM. Statistics of interest were calculated from the simulated
and observed data for comparison; for example, the 5th, 50th
(median), and 95th percentiles of the distributions of the
dexmedetomidine concentrations within discrete bins (ranges) of
time, treatment group, and age were calculated. These percentiles
of the simulated concentrations were then plotted versus time since
the end of the maintenance infusion, with the original observed
dataset and/or percentiles based on the observed data overlaid to
visually assess concordance between the model-based simulated data
and the observed data.
[0406] Due to the wide range of doses used in these studies and the
spectrum of subjects with regard to age (and weight), the
prediction-corrected VPC, as suggested by Bergstrand, et al, with
bins defined by time, treatment group, and age, was utilized. (See
AAPS J. 2011; 13(2):143-151). This technique provides an enhanced
ability to diagnose possible model misspecification by removing the
variability introduced in an ordinary VPC when binning across a
potentially large variability in dose or other influential
covariates. A total of 1448 dexmedetomidine concentration records
from 131 subjects and 3 studies were received. After exclusions,
1279 dexmedetomidine concentrations collected from 120 subjects in
these studies were available for analysis (Table 44).
TABLE-US-00046 TABLE 44 Data Disposition for Each Study Included in
the Population Pharmacokinetic Analysis Number Remaining Following
the Samples Subjects Subjects Excluded Excluded Affected Excluded
Samples Subjects Example 1 Study Dexmedetomidine NA NA NA NA 37
randomized subjects Randomized subjects with no 0 2 2 NA 34
concentration records Dexmedetomidine concentration NA NA NA 228 34
records received from Hospira, Inc. Missing concentration values 28
8 4 200 30 All concentrations below lower limit 27 4 4 173 26 of
quantitation Sub-total prior to outlier exclusions NA NA NA NA NA
Improbable concentrations based on 17 5 2 156 24 EDA plots.sup.a
Observations associated with 3 2 0 153 24 extremely high weighted
residual values during model development.sup.a Total remaining NA
NA NA 153 24 Example 5 Study Dexmedetomidine randomized NA NA NA NA
36 subjects Dexmedetomidine concentration NA NA NA 479 NA records
received from Hospira, Inc. Concentrations below lower limit of 36
36 0 443 36 quantitation Sub-total prior to outlier exclusions NA
NA NA 443 36 Observations associated with 5 4 0 438 36 weighted
residual values >7 during base model development.sup.a Subjects
with extremely long bypass 11 1 1 427 35 time.sup.a, b Total
remaining NA NA NA 427 35 Example 3 Study Dexmedetomidine
randomized NA NA NA NA 59 subjects Dexmedetomidine concentration Na
NA NA 741 NA records received from Hospira, Inc. Missing
concentration value 9 6 0 732 59 Pre-dose concentrations below
lower 57 57 0 675 59 limit of quantitation All concentrations below
lower limit 12 1 1 663 58 of quantitation Sub-total prior to
outlier exclusions NA NA NA 663 58 Extremely high concentrations
noted 4 2 0 659 58' during EDA.sup.a Observations associated with
23 16 0 636 58 weighted residual values >7 during base model
developmenta Subjects excluded from analysis due 9 3 3 627 55 to
infusion length shorter than allowed per protocol or lack of
samples collected.sup.a Implausible concentration value.sup.a 1 1 0
626 55 Subject to extremely high CL value.sup.a 11 1 1 615 54 Total
remaining NA NA NA 615 54 Total prior to outlier exclusions.sup.a
NA NA NA 1279 120 Total for pooled data NA NA NA 1195 113
Abbreviations: EDA, exploratory data analysis; NA, not applicable.
.sup.aNote: Rows representing observations designated as outliers.
.sup.bSu F, Nicolson SC, Gastonguay MR, et al. Population
pharmacokinetics of dexmedetomidine in infants after open heart
surgery. Anesth Analog. 2010; 110(5): 1383-1392.
[0407] Table 45 summarizes the numbers of subjects and
dexmedetomidine concentration values included in the analysis, by
study and randomized treatment group.
TABLE-US-00047 TABLE 45 Summary of the Numbers of Subjects and
Dexmedetomidine Concentrations, by Study and Dexmedetomidine
Treatment Group Dexmedetomidine Treatment Number Group (Loading
Number of Dose + Maintenance of Concen- Study Infusion Rate)
Subjects trations Example 1 0.05 .mu.g/kg + 0.05 .mu.g/kg/h 10 63
0.10 .mu.g/kg + 0.10 .mu.g/kg/h 8 55 0.20 .mu.g/kg + 0.20
.mu.g/kg/h 8 55 Subtotals for Example 1 26 173 Example 5 0.35
.mu.g/kg + 0.25 .mu.g/kg/h 12 139 0.70 .mu.g/kg + 0.50 .mu.g/kg/h
12 152 1.00 .mu.g/kg + 0.75 .mu.g/kg/h 12 152 Subtotals for Example
5 36 443 Example 3 0.25 .mu.g/kg + 0.20 .mu.g/kg/h 15 169 0.50
.mu.g/kg + 0.40 .mu.g/kg/h 14 159 1.00 .mu.g/kg + 0.70 .mu.g/kg/h
15 167 1.00 .mu.g/kg + 2.00 .mu.g/kg/h 14 168 Subtotals for Example
3 58 663 Overall 120 1279
[0408] Subject demographic characteristics, overall and by study,
are shown in Table 46.
TABLE-US-00048 TABLE 46 Summary of Demographic Characteristics, by
Study Example 1 Example 5 Example 3 Subject Characteristic Study
Study Study Overall Age (y) Mean (SD) 0.041 (0.029) 0.716 (0.404)
7.397 (4.193) 3.799 (4.555) Median 0.036 0.631 6.702 1.560 Min, Max
0.01, 0.13 0.21, 2.65 2.07, 16.97 0.01, 16.97 n 26 36 58 120 Weight
Mean (SD) 2.905 (0.879) 7.625 (1.802) 27.320 (20.140) 16.122
(17.791) (kg) Median 3.165 7.040 20.250 10.350 Min, Max 1.12, 4.35
5.10, 11.90 9.98, 99.00 1.12, 99.00 n 26 36 58 120 Ethnicity, White
20 (76.9) 23 (63.9) 23 (39.7) 66 (55.0) n (%) Black 9 (25.0) 9
(25.0) 6 (10.3) 15 (12.5) Asian 1 (2.8) 1 (2.8) 1 (2.8) 1 (0.8)
American 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.8) Indian 2 (5.6) 2 (5.6) 2
(5.6) 32 (26.7) Hispanic 1 (3.8) 1 (2.8) 1 (2.8) 5 (4.2) Other
Gender, Male 19 (73.1) 20 (55.6) 27 (46.6) 66 (55.0) n (%) Female 7
(26.9) 16 (44.4) 31 (53.4) 54 (45.0)
[0409] Overall, slightly more than one-half of the subjects were
male (55%), with a median age of 1.56 years (range of 0.01 to 16.97
years) and a median weight of 10.35 kg (range of 1.12 to 99 kg).
The majority of the subjects were Caucasian (55%). For the most
part, the ranges of age and weight represented in the 3 studies
comprise a continuum of maturation and size from very small infants
to nearly adults with little or no overlap in these characteristics
between studies. As shown in Table 47, the median alanine
aminotransferase level was 21.0 U/L for the subjects overall, with
a slightly higher median in the Example 5 subjects (24.0 U/L)
compared to the median values in the Example 3 (19.0 U/L) and
Example 1 (19.5 U/L) subjects. The median value for total bilirubin
in the overall group was 0.5 mg/dL; although, total bilirubin
levels were considerably higher in the Example 1 subjects (median
total bilirubin level of 4.65 mg/dL).
TABLE-US-00049 TABLE 47 Summary of Laboratory Values, by Study
Study Example 5 Study Subject Characteristic Example 1 Study
Example 3 Overall Alanine Mean (SD) 27.077 (22.337) 25.917 (8.917)
26.828 (21.881) 26.608 (18.914) aminotransferase Median 19.500
24.000 19.000 21.000 (U/L) Min, Max 7.00, 84.00 8.00, 52.00 9.00,
144.00 7.00, 144.00 n 26 36 58 120 Total bilirubin Mean (SD) 4.871
(3.708) 0.347 (0.146) 0.591 (0.425) 1.445 (2.503) (mg/dL) Median
4.650 0.300 0.500 0.500 Min, Max 0.20, 14.60 0.10, 0.70 0.17, 2.20
0.10, 14.60 n 27 36 58 120
[0410] Table 48 shows the summary statistics for cardiac status of
the subjects (cardio-pulmonary bypass and heart ventricle
physiology), administration of albumin infusion or medications
known to be glucuronidation pathway inhibitors, and site of blood
sampling for pharmacokinetics analysis of dexmedetomidine
concentrations.
TABLE-US-00050 TABLE 48 Summary of Cardiac Status, Concomitant
Medications, and Site of Pharmacokinetic Sampling Study Example
Study Example 5 Example Subject Characteristic 1 Study 3 Overall
Cardio-pulmonary bypass, No 21 (80.8) 0 (0.0) 17 (29.3) 38 (31.7) n
(%) Yes 5 (19.2) 36 (100.0) 41 (70.7) 82 (68.3) Ventricle, n (%)
Single 0 (0.0) 19 (52.8) 0 (0.0) 19 (15.8) Double 26 (100.0) 17
(47.2) 58 (100.0) 101 (84.2) Albumin infusion, n (%) No 19 (73.1)
36 (100.0) 46 (79.3) 101 (84.2) Yes 7 (26.9) 0 (0.0) 12 (20.7) 19
(15.8) Glucuronidation pathway No 6 (23.1) 0 (0.0) 7 (12.1 13
(10.8) inhibitors, n (%) Yes 20 (76.9) 36 (100.0) 51 (87.9) 107
(89.2) Site of sampling.sup.a Venous 66 (38.2) 443 (100.0) 663
(100.0) 1172 (91.6) Arterial 95 (54.9) 0 (0.0) 0 (0.0) 95 (7.4)
Capillary 12 (6.9) 0 (0.0) 0 (0.0) 12 (0.9)
[0411] All Example 5 subjects and most Example 3 subjects (70.7%)
underwent cardio-pulmonary bypass, but relatively fewer subjects in
the Example 1 study (19.2%) underwent this procedure. Subjects with
single ventricle physiology were only present in the Example 5
study (52.8%). Overall, the majority of subjects (84.2%) did not
receive an albumin infusion, and 89.2% of subjects received
co-medications known to be glucuronidation pathway inhibitors 24 h
prior to surgery, during surgery, or during dexmedetomidine
treatment.
[0412] Plasma samples for the determination of dexmedetomidine
concentrations were collected around the time of the loading dose,
near the start and during the maintenance infusion, and after
discontinuation of the maintenance infusion according to the
pre-specified schedules for the studies in Examples 1, 3, and 5.
The number of plasma dexmedetomidine concentrations contributed per
individual subject ranged from 1 to 13 across studies with the most
samples per subject in Example 5 (10 to 13, median of 13), a
similar amount per subject in Example 3 (1 to 12, median of 12),
and less from Example 1, as expected (5 to 7, median of 7 samples
per subject). The overall range of dexmedetomidine doses for both
the loading dose and maintenance infusion was large (56 ng to
140,000 ng and 357 ng to 828,800 ng, respectively). Summary
statistics for the dexmedetomidine loading doses and maintenance
infusion doses are shown in Tables 5A, 27A, and 37.
[0413] Looking across all of the treatment groups, the median total
dexmedetomidine doses for the Example 1, 3, and 5 studies were 2184
ng, 36,011 ng, and 120,550 ng, respectively. The infusion durations
for the loading dose (median of 0.167 h in almost all treatment
groups) and maintenance doses (median ranged from approximately 6 h
to 9 h in almost all treatment groups) were quite consistent across
the studies.
[0414] FIGS. 16A-C present lineplots of plasma dexmedetomidine
concentrations versus time since the start of the loading dose
infusion for each treatment group in the 3 studies. In FIGS. 17A-C,
lineplots of dexmedetomidine concentrations versus time since the
end of the maintenance infusion are shown for each treatment group.
Based on the concentrations measured after the end of the infusion,
these plots suggest that a 2-compartment model would likely be
adequate to describe these data. Although this finding is
consistent with a previous report describing the population
pharmacokinetics for dexmedetomidine in infants, other types of
models were additionally examined.
[0415] FIGS. 18A-B show a semilogarithmic scatterplot of
dose-normalized dexmedetomidine plasma concentrations versus time
since the end of the maintenance infusion stratified by study,
demonstrating that dexmedetomidine pharmacokinetics was generally
similar across the treatment groups from the Example 3 and Example
5 studies. Smoothing splines are used in these plots to illustrate
the trend over time within each treatment group. There appears to
be a trend towards higher dose-normalized dexmedetomidine
concentrations in the lowest dose group (0.05 mg/kg+0.05 mg/kg/h)
from the Example 1 study, however, the pattern is less evident in
the 0.10 mg/kg+0.10 mg/kg/h and 0.20 mg/kg+0.20 mg/kg/h dose
groups.
[0416] The percent of BLQ samples within the Example 5 and Example
3 studies were quite similar (slightly less than 10% in each study
and 3% and 5% overall, respectively), although the percent of
samples that were BLQ was much higher in the Example 1 study
(approximately 40% of the study and 5% overall). The BLQ samples
were retained in the dataset and set to a value of one-half the
LLOQ of the assay used to determine the dexmedetomidine
concentration in the particular study.
[0417] The pooled data from Studies Example 3 and Example 5 were
initially used for model development. Based on previous modeling
efforts and the exploratory analysis results (in particular, the
scatterplots of dexmedetomidine concentrations versus time), a
2-compartment model, as well as 1- and 3-compartment linear models,
were fit to the data. (See Su et al.) A mammillary 2-compartment
model best described the data, with IIV estimated on CL, Vc, Q, and
volume of the Vp using exponential error models. Residual
variability was estimated separately for each study using a
combined additive and constant coefficient of variation error
model.
[0418] Based on literature recommendations, fixed allometric
exponents for scaling of body weight were included for the
clearance and volume parameters (0.75 for CL and Q and 1.0 for Vc
and Vp). These standard exponents predict a less than proportional
increase in CL and Q with increasing body weight and a proportional
increase in Vc and Vp with increasing body weight. A negative
linear relationship between and age and Vp, as well as a negative
power function to relate age and Q, were also included in the base
structural pharmacokinetic model describing the data from these 2
studies.
[0419] Pharmacokinetic parameter estimates and standard errors of
the estimates for the fit of the 2-compartment model to these data
are presented in Table 49.
TABLE-US-00051 TABLE 49 Parameter Estimates and Standard Errors
From the Dexmedetomidine Pharmacokinetic Model Developed Using
Example 5 and Example 3 Data Only Magnitude of Interindividual
Final Parameter Variability Estimate (% CV) Population % Final %
Parameter Mean SEM Estimate SEM CL (L/h).sup.a 18.5 3.5 30.76 18.3
Vc (L).sup.b 18.9 8.9 68.26 17.0 Intercompartmental CL (L/h).sup.c
35.9 15.8 Exponent of power relationship -0.509 33.6 117.05 24.9
between Q and age.sup.c Vp (L).sup.d 19.1 9.3 Slope of linear age
effect on -1.43 15.3 27.15 56.7 Vp (L/y).sup.d Ratio of additive to
11.8 14.7 NA NA proportional RV: Example 5 Ratio of additive to
42.1 15.5 NA NA proportional RV: Example 3 RV Example 5.sup.e
0.0363 16.9 NA NA RV Example 3.sup.f 0.0712 19.1 NA NA Minimum
value of the objective function = 9930.466 Abbreviations: CL,
elimination clearance; IIV, interindividual variability; NA, not
applicable; % CV, coefficient of variation expressed as a
percentage; % SEM, standard error of the mean expressed as a
percentage; Q, intercompartmental clearance; RV, residual
variability; Vc, volume of the central compartment; Vp, volume of
the peripheral compartment; WTKG, weight in kg. a Typical CL = 18.5
.times. ( WTKG 19.8 ) 0.75 ##EQU00001## b Typical Vc = 18.9 .times.
( WTKG 19.8 ) ##EQU00002## c Typical Q = 35.9 .times. ( WTKG 19.8 )
0.75 .times. ( age 4.8 ) - 0.509 ##EQU00003## d Typical Vp = 19.1
.times. ( WTKG 19.8 ) - 1.43 .times. ( age - 4.8 ) ##EQU00004##
.sup.eResidual variability estimate is expressed as a variance. The
corresponding % CV for RV in Example 5 ranges from 108% CV at 2.12
ng/L (one-half the lower assay limit) to 19% CV at 700 ng/L.
.sup.fResidual variability estimate is expressed as a variance. The
corresponding % CV for RV in Example 3 ranges from 79% CV at 15.12
ng/L (one-half the lower assay limit) to 27% CV at 2000 ng/L.
[0420] Most parameters were estimated with reasonable precision
(standard error of the mean expressed as a percentage [%
SEM]<34%), with the exception of the IIV for Vp, which was
estimated with slightly poorer precision (% SEM=56.7%). Diagnostic
plots indicated a good fit to the data, with no apparent biases,
except a slight degree of under-prediction of concentrations
measured more than 10 h after the end of the infusion. This
under-prediction may be due to the prediction of late samples at
levels below the limit of quantitation of the assay, where the
observed data were fixed to values of one-half the assay limit.
[0421] Model development was continued with the addition of the
Example 1 data to the pooled Example 3 and Example 5 dataset. When
the model developed using the Example 5 and Example 3 data was
applied to the pooled dataset including Example 1, high
correlations were initially observed between many of the
parameters. Due to the difference in weight and age of the subjects
from Example 1 as compared to the older subjects from the other two
studies, the model including only the allometric functions of
weight was evaluated next, removing the additional effects of age
that were included in the previous model. After refining this model
with the pooled dataset first, the effect of maturation on various
pharmacokinetics parameters was then addressed.
[0422] In the evaluation of maturation effects on dexmedetomidine
pharmacokinetics, shifts in the allometric exponents were tested
for pre-term subjects (that is, those with gestational
age.ltoreq.28 weeks from Example 1), as well as neonates (that is,
subjects less than 1 month of age, regardless of gestational age)
as compared to all other subjects. Shifts in the allometric
exponents for CL and Vc for neonates were associated with the
largest reduction in the MVOF (approximately 48 points) and good
precision of parameter estimates and were, therefore, retained in
the model. Both Q and Vp were additionally found to be
statistically significantly related to age. A power function was
used to describe the negative relationships between these
parameters and age (that is, both parameters decrease with
increasing age).
[0423] The final base structural pharmacokinetics model for the
pooled dataset of Examples 1, 3, and 5 was a 2-compartment model
with IIV estimated on CL, Q, Vc, and Vp using exponential error
models, separate additive and constant coefficient of variation RV
models for each study, fixed allometric exponents (as stated above)
on the clearance and volume parameters with an additional shift on
the CL and Vc exponents for neonates, age effects on Q and Vp
described by power functions (both decrease with increasing age),
and covariance parameters for the IIVs on CL and Vp, and the IIVs
on Q and Vc. The final base structural 2-compartment model and
standard errors are presented in Table 50.
TABLE-US-00052 TABLE 50 Parameter Estimates and Standard Errors
From the Dexmedetomidine Base Structural Model Magnitude of
Interindividual Final Parameter Variability Estimate (% CV)
Population % Final % Parameter Mean SEM Estimate SEM CL (L/h).sup.a
11.5 3.5 Proportional shift in allometric 0.480 20.88 35.07 17.2
exponent for CL for neonates.sup.a Vc (L).sup.b 9.46 11.4
Proportional shift in allometric 0.513 56.7 53.48 21.6 exponent for
Vc for neonates.sup.b Intercompartmental CL (L/h).sup.c 71.0 41.4
Exponent for power function -0.286 37.8 164.32 34.3 effect of age
on Q.sup.c Vp (L).sup.d 15.2 8.8 Exponent for power function -0.291
12.2 47.12 23.3 effect of age on Vp.sup.d Ratio of additive to 8.73
40.3 NA NA proportional RV: Example 1 Ratio of additive to 12.3
14.4 NA NA proportional RV: Example 5 Ratio of additive to 40.8
16.8 NA NA proportional RV: Example 3 cov(IIV in CL, IIV in Vp)
0.124 21.5 NA NA cov(IIV in Q, IIV in Vc) 0.814 22.6 NA NA RV
Example 1.sup.e 0.194 22.6 NA NA RV Example 5.sup.f 0.0359 16.4 NA
NA RV Example 3.sup.g 0.0684 18.7 NA NA Minimum value of the
objective function = 11069.294 Abbreviations: CL, elimination
clearance; IIV, interindividual variability; NA, not applicable;
NEO, indicator variable for neonates; % CV, coefficient of
variation expressed as a percentage; % SEM, standard error of the
mean expressed as a percentage; Q, intercompartmental clearance;
RV, residual variability; Vc, volume of the central compartment;
Vp, volume of the peripheral compartment; WTKG, weight in kg. a
Typical CL = 11.5 .times. ( WTKG 10.35 ) [ 0.75 .times. ( 1 + 0.480
.times. NEO ) ] ##EQU00005## b Typical Q = 9.46 .times. ( WTKG
10.35 ) [ 1 + 0.513 .times. NEO ] ##EQU00006## c Typical Q = 71.0
.times. ( WTKG 10.35 ) 0.75 .times. ( age 1.56 ) - 0.286
##EQU00007## d Typical Vp = 15.2 .times. ( WTKG 10.35 ) .times. (
age 1.56 ) - 0.291 ##EQU00008## .sup.eResidual variability estimate
is expressed as a variance. The corresponding % CV for RV in
Example 1 study ranges from 51% CV at 14.97 ng/L (one-half the
lower assay limit) to 44% CV at 200 ng/L. .sup.f Residual
variability estimate is expressed as a variance. The corresponding
% CV for RV in Example 5 study ranges from 112% CV at 2.12 ng/L
(one-half the lower assay limit) to 19% CV at 700 ng/L.
.sup.gResidual variability estimate is expressed as a variance. The
corresponding % CV for RV in Example 3 study ranges from 75% CV at
15.12 ng/L (one-half the lower assay limit) to 26% CV at 3000
ng/L.
[0424] With the exception of the parameter for the proportional
shift in the allometric exponent for Vc for neonates (% SEM of
56.7%), the other fixed and random effect model parameters were all
estimated with reasonable precision (most % SEMs<40%).
Goodness-of-fit plots are shown in FIGS. 19A-B for the base
structural model for the pooled dataset of Examples 1, 3, and 5.
Diagnostic plots indicate a good fit to the pooled data and a lack
of substantial bias.
[0425] The following covariates were tested on CL and Vc: gender,
ethnicity, cardio-pulmonary bypass use, albumin infusion
(presence), and site of sampling (arterial versus venous versus
capillary). The following covariates were tested on CL only:
alanine aminotransferase, total bilirubin, glucuronidation pathway
inhibitors (presence), and heart physiology (single versus double
ventricle). The effect of ethnicity was modeled as Caucasian versus
Hispanic versus all "other" race groups (Asian, black) that were
combined due to the small sample sizes. Each continuous covariate
effect was tested in NONMEM using a linear and power model.
Categorical covariates were tested using additive shifts.
Delta-parameter plots were generated to illustrate the possible
relationships between the remaining unexplained IIV in CL or Vc and
the covariates of interest. No obvious trends are apparent
indicating likely parameter-covariate relationships. Furthermore,
the lack of trend in the plots for age and weight indicate that
these factors are adequately accounted for in the base structural
model, which includes allometric weight relationships and
additional effects of maturation. Although the effect of several
covariates (total bilirubin, albumin infusion, and alanine
aminotransferase on CL) was statistically significant (P
value<0.05 based on a reduction in the MVOF following their
inclusion in the model), none of these covariate effects was also
associated with a.gtoreq.5% reduction in IIV in CL.
[0426] As a result of the univariate forward selection results, no
additional covariates were added to the base model. Therefore, the
backward elimination step was not performed and this base model was
next evaluated for further refinement and simplification. Next, the
base structural model following forward selection was checked for
possible simplifications in an effort to identify the most
appropriate and parsimonious model which adequately characterized
these data. Removal of the shift for the allometric exponent on Vc
for neonates resulted in a non-statistically significant increase
in the MVOF of 1.991 (P value>0.05) and was, therefore, removed
from the model. Further simplification of the RV model for Example
1 to a constant coefficient of variation error model was also
performed; this simplification was also associated with a
non-statistically significant increase in the MVOF of 1.331 (P
value>0.05) and was, therefore, implemented.
[0427] Goodness-of-fit diagnostic plots were examined for model
misfit. Several alternative methods for handling of BLQ samples
were also evaluated, including Beals M3 method and the exclusion of
BLQ samples after the first one in a sequence, but these attempts
did not minimize successfully or did not result in model
improvement. A further assessment of the model including all
outliers did not result in successful minimization; therefore, the
observations identified as outliers during model development were
permanently excluded. A simulation-based prediction-corrected VPC
was performed using the final pharmacokinetics model, simulating
1000 replicates of the analysis dataset. This VPC method was used
to improve the ability to diagnose possible model misspecification
by removing the variability resulting from the broad range of doses
and ages/weights of subjects. Therefore, for the purposes of the
prediction correction, discrete bins based on time since the end of
the infusion, dexmedetomidine treatment group, and age were
defined.
[0428] FIG. 20 illustrates the 90% prediction interval, derived
from the 1000 simulated datasets, overlaid on the observed
dexmedetomidine concentrations versus time since the end of the
maintenance infusion. Concentrations measured prior to the end of
the maintenance infusion are presented with a negative value for
the time since the end of the maintenance infusion. The majority of
the observed data falls within the prediction interval. The
percentage of the observed concentrations below the 5th percentile
was 6.3% and the percentage above the 95th percentiles was 4.7%.
The VPC indicates no apparent biases in the overall model fit by
comparing the simulated data (based on the model) to the raw
data.
[0429] FIG. 21 illustrates a comparison of the 5th, 50th, and 95th
percentile of the prediction-corrected observed and model-based
simulated data. This plot also confirms the high degree of
concordance between the simulation-based data and the observed
data, wherein the 50th percentiles of the observed and simulated
data track very well across the entire range of time. For the
purposes of the VPC, the simulated concentrations were treated in a
manner identical to the observed concentrations, whereby values
less than the assay limit for the study were set to one-half the
appropriate limit.
[0430] The final population pharmacokinetics model was a
2-compartment model with IIV estimated on CL, Q, Vc, and Vp using
exponential error models, fixed allometric exponents on the
clearance (0.75 for CL and Q) and volume of distribution (1.0 for
Vc and Vp) parameters, with an additional shift on the CL exponent
for neonates, age effects on Q and Vp described by power functions
(both decrease with increasing age), covariance terms for the IIVs
on CL and Vp, and the IIVs on Q and Vc, separate additive plus
constant coefficient of variation error models for Studies Example
3 and Example 5, and a constant coefficient of variation error
model for the Example 1 study.
[0431] The parameter estimates for the final population
pharmacokinetics model for dexmedetomidine are provided in Table
51.
TABLE-US-00053 TABLE 51 Parameter Estimates and Standard Errors
From the Dexmedetomidine Final Population Pharmacokinetic Model
Magnitude of Interindividual Final Parameter Variability Estimate
(% CV) Population % Final % Parameter Mean SEM Estimate SEM CL
(L/h).sup.a 11.4 3.5 Proportional shift in allometric 0 .468 19.3
35.07 17.3 exponent for CL for neonates.sup.a Vc (L).sup.b 9.20
11.6 54.13 21.6 Intercompartmental CL (L/h).sup.c 70.5 43.7 37.3
Exponent for power function -0.293 39.6 163.40 effect of age on
Q.sup.c Vp (L).sup.d 15.2 8.8 24.3 Exponent for power function
-0.282 12.9 47.33 effect of age on Vp.sup.d Ratio of additive to
8.79 15.8 NA NA proportional RV: Example 5 Ratio of additive to
27.4 54.4 NA NA proportional RV: Example 3 cov(IIV in CL, IIV in
Vp) 0.124 22.8 NA NA cov(IIV in Q, IIV in Vc) 0.818 23.6 NA NA RV
Example 1.sup.e 0.214 20.4 NA NA RV Example 5.sup.f 0.0358 16.4 NA
NA RV Example 3.sup.g 0.0682 18.8 NA NA Minimum value of the
objective function = 11072.619 Abbreviations: CL, elimination
clearance; IIV, interindividual variability; NA, not applicable;
NEO, indicator variable for neonates; % CV, coefficient of
variation expressed as a percentage; % SEM, standard error of the
mean expressed as a percentage; Q, intercompartmental clearance;
RV, residual variability; Vc, volume of the central compartment;
Vp, volume of the peripheral compartment; WTKG, weight in kg. a
Typical CL = 11.4 .times. ( WTKG 10.35 ) [ 0.75 .times. ( 1 + 0.468
.times. NEO ) ] ##EQU00009## b Typical CL = 9.20 .times. ( WTKG
10.35 ) ##EQU00010## c Typical CL = 70.5 .times. ( WTKG 10.35 )
0.75 .times. ( age 1.56 ) - 0.293 ##EQU00011## d Typical Vp = 15.2
.times. ( WTKG 10.35 ) .times. ( age 1.56 ) - 0.282 ##EQU00012##
.sup.eResidual variability estimate is expressed as a variance. The
corresponding % CV for RV in Example 1 is 46% CV. .sup.fResidual
variability estimate is expressed as a variance. The corresponding
% CV for RV in Example 5 ranges from 111% CV at 2.12 ng/L (one-half
the lower assay limit) to 19% CV at 700 ng/L. .sup.gResidual
variability estimate is expressed as a variance. The corresponding
% CV for RV in Example 3 ranges from 75% CV at 15.12 ng/L (one-half
the lower assay limit) to 26% CV at 3000 ng/L.
[0432] All fixed effect parameters were estimated with good
precision (% SEMs<20%), with the exception of those associated
with Q, which were estimated with slightly poorer precision (% SEMs
of around 40%). Random effects were also estimated with good
precision (most % SEMs<25%, except IIV in Q with % SEM=37%).
Interindividual variability in CL, Vc, and Vp was moderate, ranging
from 35% CV to 55% CV. Unexplained IIV in Q was very high at 163%
CV. Overall, RV was the lowest in the Example 5 data (around 19%
CV) and slightly higher in the Example 3 data (26% CV), but in both
studies was considerably larger at low of variation RV model was
found to adequately describe the data from Example 1, with a
relatively higher estimate of 46% CV, regardless of concentration
level.
[0433] The equations describing the relationships between the
typical dexmedetomidine parameter values and the subject factors
included in the model (that is, those relating to weight and age)
are provided in Equation 1, Equation 2, Equation 3, and Equation
4.
Typical CL j = 11.4 .times. ( WTKG j 10.35 ) [ 0.75 .times. ( 1 +
0.468 .times. NEO j ) ] ( 1 ) Typical Vc j = 9.20 .times. ( WTKG j
10.35 ) ( 2 ) Typical Q j = 70.5 .times. ( WTKG j 10.35 ) 0.75
.times. ( age j 1.56 ) - 0.293 ( 3 ) Typical Vp j = 15.2 .times. (
WTKG j 10.35 ) .times. ( age j 1.56 ) - 0.282 ( 4 )
##EQU00013##
[0434] Where:
[0435] CL.sub.j is the typical value of dexmedetomidine clearance
in the jth subject predicted by the model,
[0436] Vc.sub.j is the typical value of dexmedetomidine volume of
the central compartment in the jth subject predicted by the
model,
[0437] Q.sub.j is the typical value of dexmedetomidine
intercompartmental clearance in the jth subject predicted by the
model,
[0438] Vp.sub.j is the typical value of dexmedetomidine volume of
the peripheral compartment in the jth subject predicted by the
model,
[0439] age.sub.j is the age, in years, of the jth subject,
[0440] WTKG.sub.j is the weight, in kg, of the jth subject, and
[0441] NEO.sub.j is an indicator variable with a value of 1 for
neonate subjects and 0 otherwise.
[0442] Goodness-of-fit plots for this model are provided in FIGS.
22A-D for the entire population. At the level of the overall
dataset, these diagnostic plots indicate a reasonably unbiased fit
of the model to the dataset, with a slight underprediction of the
samples collected more than 10 h after the end of the infusion.
This is apparent in the grouping of points that are associated with
positive weighted residuals after 10 h in the plot of weighted
residuals versus time since end of the infusion. In addition, these
plots provide support for the selected models for RV based on the
lack of trend or pattern in the plots of individual weighted
residuals versus individual predicted concentrations. To further
illustrate the appropriateness of the model across the treatment
groups and age range of the subjects, additional goodness-of-fit
plots were prepared stratified by treatment group and by age group.
Although some treatment and age groups represent very small sample
sizes, these plots indicated no substantial persistent trends of
misfit or bias across the range of doses or age levels.
Calculations of the shrinkage of the empirical Bayesian estimate
distributions indicate no concern over excessive shrinkage for any
of the pharmacokinetics parameters as the estimates are all
indicative of low shrinkage (that is, 3.5% for CL, 13.7% for Vc,
13.7% for Q, and 12.6% for Vp).
[0443] Pairwise scatterplots of these terms are provided in FIG.
25. These plots demonstrate the modeled correlations between the
IIV in CL and Vp and between the IIV in Q and Vc, as well as a lack
of substantial relationship between other pairs of terms.
[0444] The final base structural pharmacokinetics model for
dexmedetomidine using the pooled data from the 3 studies was a
2-compartment model with fixed allometric exponents on the
clearance and volume parameters, an additional shift on the CL and
Vc exponents for neonates, and age effects on Q and Vp. The
allometric weight adjustments using the fixed coefficients of 0.75
for CL and 1 for volume terms were based on a well-described
scientific framework that can be related to basic physiologic
functions, and have been used frequently in pediatric
pharmacokinetics analyses. Because the allometric coefficients were
fixed for maturation based on age could be delineated from the
effect of size. With the inclusion of the Example 1 study data in
the analysis, the shifts on CL and Vc were included for the neonate
group to correct for maturation only in these youngest subjects. In
addition, the age effects on Q and Vp (decrease with increasing
age) were included in the model for all subjects, and are
consistent with known age-dependent changes in proportions of body
water and fat which influence the distribution of drugs. Overall,
this covariate approach avoided problems with co-linearity between
size and age by first addressing size as a fixed allometric
exponent, and then using age to describe maturation, as has been
previously suggested in the literature.
[0445] Additional covariate effects were tested on dexmedetomidine
CL and Vc based on clinical interest and physiologic plausibility;
however, no effect met the pre-specified criteria for inclusion in
the model. In a previously developed 2-compartment population
pharmacokinetics model of dexmedetomidine in infants (aged 1 to 24
months) after open heart surgery, significant covariate effects
included total bypass time on CL and Vc and ventricular physiology
(1- or 2-ventricle) on CL, in addition to fixed allometric effects
of weight on CL, Q, Vc, and Vp. There are several factors that may
contribute to the difference in findings between the 2
analyses.
[0446] Su et al. used a full model approach for covariate selection
while the current analysis used step-wise hypothesis testing, with
fairly stringent criteria that required achievement of both
statistical significance as well as a 5% reduction in IIV. (See
Anesth Analg. 2010; 110(5):1383-1392.) The data available for
covariate assessment also differed from Su et al., where total
bypass time was determined to be a significant covariate as a
continuous variable; the current analysis was limited to evaluation
of CPB use as a dichotomous variable indicating occurrence or lack
of occurrence.
[0447] Since no additional covariates were found to be significant,
the final pharmacokinetics model was structurally similar to the
base model with the exception of 2 model refinements consisting of
the removal of the allometric exponent on Vc for neonates and
simplification of the RV model for the Example 1 study to a
constant coefficient of variation error model. The degree of RV was
relatively higher in the Example 1 study data (46% CV) compared to
the Study Example 3 (26% CV) and Example 5 data (19% CV). Different
levels of enzyme maturation in the subjects in the Example 1 study
are a likely contributing factor to the increased variability. In
addition, comparatively more data was collected after low
dexmedetomidine doses in the Example 1 study resulting in an
increased frequency of plasma concentrations in the lower range of
the assay where variability tends to be greater.
[0448] Overall, all fixed effect parameters were precisely
estimated except for those associated with Q (% SEMs approximately
40%). The estimate of Q was considerably higher (70.5 L/h) and the
unexplained IIV in Q was also quite high (163% CV) compared to an
initial model based on data from only Studies Example 3 and Example
5 (Q=35.9 L/h, IIV in Q=117% CV). This finding may be related to
the sparser nature of the data added from the Example 1 study and,
as a result, the plasma sampling for dexmedetomidine concentrations
was less informative to the 2-compartment model parameters in the
neonates.
[0449] The final pharmacokinetics model for dexmedetomidine was a
2-compartment model as has been previously described in other
investigations of pediatric subjects. Given the remaining slight
bias towards underprediction of concentrations obtained at later
sampling times after the end of the maintenance infusion seen in
the goodness-of-fit plots (FIGS. 22A-D), a 3-compartment model was
also evaluated using the concentration data from Studies Example 3
and Example 5. However, the 3-compartment model fit was essentially
identical to the 2-compartment model, and the underprediction bias
(FIG. 18) was not corrected. A 3-compartment model was not
attempted with the addition of the Example 1 study data since the
sparser data from neonates would be even less informative at the
later sampling times.
[0450] Comparison of fixed effect parameters from the 2-compartment
model published by Su et al. (based on only 35 subjects from the
Example 5 study ranging in age from 1 to 24 months) for a subject
aged 7.7 months, weighing 7 kg, and with the median value for total
bypass time (57 minutes) with those from the final pharmacokinetics
model developed herein (based on 115 subjects ranging in age from
less than 1 week to 17 y) revealed fairly similar estimates, except
for Q. Values for CL, Vc, Q, and Vp were 7.26 L/h, 8.4 L, 24.1 L/h,
and 10.2 L from the Su et al. model compared to 8.5 L/h, 6.22 L,
68.21 L/h, and 13.21 L from the current analysis. Estimates of the
initial distribution (.alpha.) and terminal elimination ((.beta.)
half-lives in the current analysis were 3.2 minutes and 1.6 h for a
pediatric subject with the median age and weight of 1.56 y and
10.35 kg, respectively, and 7.5 minutes and 1.8 h for a 17 year
old, 70-kg subject. These results are generally similar to the
ranges of initial distribution half-life (4.08 minutes to 9
minutes) and terminal elimination half-life (1.6 h to 2.65 h),
previously reported for dexmedetomidine given as 1 .mu.g/kg for 5
minutes or 10 minutes, or 0.2 .mu.g/kg/h to 0.7 .mu.g/kg/h
infusion. (See Diaz et al., Pediatr Crit Care Med. 2007; 8:419-424;
Petroz et al., Anesthesiology. 2006; 105:1098-1110; and Vilo et
al., Br J Anaesthesia. 2008; 100:697-700).
[0451] It is also of interest to compare CL and volume of
distribution (Vc+Vp) across the age range of the 6 pediatric age
groups represented in the 3 studies of dexmedetomidine contributing
to the pharmacokinetics model (28 weeks to <1 month, 1 month to
<6 months, 6 months to <12 months, 12 months to <24
months, 2 years to <6 years, and 6 years to <17 years). FIG.
23 and FIG. 24 (upper panels) provide the geometric means and 95%
confidence intervals for the individual Bayesian estimates of
dexmedetomidine CL and volume of distribution plotted at the
midpoint of each age group, with the corresponding weight-adjusted
estimates for the pharmacokinetics parameter depicted similarly in
the lower panels. A line for the population model-based typical
value of each parameter versus age is overlaid in each plot.
[0452] Table 52 and Table 53 provide summary statistics for the
individual Bayesian parameter estimates and the model-predicted
typical value estimates by age group for dexmedetomidine CL,
weight-adjusted CL, volume of distribution, and weight-adjusted
volume of distribution, respectively.
TABLE-US-00054 TABLE 52 Summary Statistics for the Individual
Bayesian Estimates and Model-Predicted Typical Values of
Dexmedetomidine Clearance and Weight-Adjusted Clearance by Age
Group Weight-Adjusted CL (L/h) CL (L/h/kg) Median Median Geo.
Predicted Geo. Predicted Weight (kg) Age (y) Mean Typical Mean
Typical Age Group (min, max) (min, max) (95% CI) Value (95% CI)
Value 28 weeks 3.12 0.029 2.71 3.04 0.991 0.976 GA-<1 month
(1.19, (0.008, (2.03, (0.810, (n = 22) 3.80) 0.077) 3.61) 1.212) 1
month- <6 months 5.99 0.332 6.95 7.56 1.213 1.263 (n = 14)
(3.15, (0.099, (5.52, (0.998, 7.00) 0.484) 8.75) 1.475) 6 months-
<12 months 7.28 0.657 8.15 8.75 1.110 1.203 (n = 16) (5.10,
(0.521, (7.05, (0.945, 9.34) 0.896) 9.43) 1.302) 12 months- <24
months 10.20 1.493 11.34 11.28 1.118 1.105 (n = 8) (8.87, (0.973,
(9.13, (0.908, 11.90) 1.651) 14.07) 1.375) 2 y-<6 y 13.75 3.548
15.88 14.11 1.108 1.026 (n = 26) (9.98, (2.070, (14.06, (1.000,
23.59) 5.761) 17.95) 1.228) 6 y-<17 y 30.20 9.887 24.46 25.45
0.796 0.843 (n = 29) (13.60, (6.032, (19.50, (0.695, 99.00) 16.967)
30.67) 0.911)
TABLE-US-00055 TABLE 53 Summary Statistics for the Individual
Bayesian Estimates and Model-Predicted Typical Values of
Dexmedetomidine Volume of Distribution and Weight-Adjusted Volume
of Distribution by Age Group Volume of Distribution Weight-Adjusted
(L) V (L/kg) Median Median Geo. Predicted Geo. Predicted Weight
(kg) Age (y) Mean Typical Mean Typical Age Group (min, max) (min,
max) (95% CI) Value (95% CI) Value 28 weeks GA- 3.12 0.029 15.38
16.90 5.634 5.418 <1 month (1.19, (0.008, (11.67, (4.456, (n =
22) 3.80) 0.077) 20.28) 7.124) 1 month- <6 months 5.99 0.332
17.26 18.91 3.012 3.160 (n = 14) (3.15, (0.099, (14.84, (2.498,
7.00) 0.484) 20.07) 3.632) 6 months- <12 months 7.28 0.657 21.27
20.10 2.895 2.763 (n = 16) (5.10, (0.521, (18.26, (2.438, 9.34)
0.896) 24.77) 3.438) 12 months- <24 months 10.20 1.493 25.29
24.23 2.493 2.376 (n = 8) (8.87, (0.973, (19.84, (1.963, 11.90)
1.651) 32.24) 3.167) 2 y-<6 y 13.75 3.548 33.51 28.24 2.338
2.054 (n = 26) (9.98, (2.070, (28.94, (2.052, 23.59) 5.761) 38.80)
2.665) 6 y-<17 y 30.20 9.887 51.51 53.19 1.677 1.761 (n = 29)
(13.60, (6.032, (39.84, (1.402, 99.00) 16.967) 66.61) 2.005)
[0453] In FIG. 23 (upper panel), the steeper slope of the profile
exhibited at the youngest age levels results from the additional
maturation covariate effect on the CL exponent for neonates, with a
shallower increase in CL evident with increasing age greater than 1
year. The weight-adjusted CL shown in the lower panel of FIG. 23
also increases between the 2 youngest age groups, but then
continues to decrease across the remaining groups. The overall
slope of the profile exhibited for volume of distribution in the
upper panel of FIG. 24 represents the net effect of increasing Vc
and Vp with increasing weight and decreasing Vp with increasing
age.
[0454] Likewise, the pronounced reduction in weight-adjusted volume
of distribution with increasing age in the youngest age groups
(FIG. 24, lower panel) is most likely attributable to the negative
effect of age on Vp (power function), while Vc remains more
constant with increasing age. This pediatric pharmacokinetics model
can be further used to extrapolate values for pediatric
pharmacokinetics parameters to values expected at usual adult ages
and weights, for comparison to typical pharmacokinetics parameter
values obtained from the previously developed adult population
pharmacokinetics model for dexmedetomidine. Based on a hypothetical
pediatric subject at the upper end of the ranges for age and weight
(that is, 17 years and 70 kg), the dexmedetomidine CL and volume of
distribution are predicted to be 47.8 L/h and 114.6 L, compared to
corresponding values of 39 L/h (mean body weight associated with
this CL was 72 kg) and 118 L as reported in the product label for
Precedex.
[0455] Similarly, dexmedetomidine CL and volume of distribution
were 35.8 L/h and 112.7 L22 in the typical subject from the adult
population pharmacokinetics analysis of long-term (>24 h)
dexmedetomidine use, and 39.4 L/h and 152 L, respectively, from the
noncompartmental analysis of this data. These extrapolated results
based on a 70-kg subject are also consistent with estimates of CL
and volume of distribution standardized to a 70-kg adult of 42.1
L/h and 125.3 L from a population pharmacokinetics analysis of
pooled data from 4 studies of dexmedetomidine in pediatric
intensive care (subjects aged 1 week to 14 years given 1 .mu.g/kg/h
to 6 .mu.g/kg/h infusion). 24 Overall, this model provides a robust
characterization of the pharmacokinetics of dexmedetomidine in
pediatrics.
[0456] The model evaluation results provide evidence that the model
is able to predict well over the entire range of dexmedetomidine
concentrations occurring during the maintenance infusion, as well
as after discontinuation. In addition, this population model is
based on the largest population of pediatric subjects, and broadest
range of ages (neonate to 17 years), maintenance doses, and
infusion durations reported to date.
[0457] The conclusions of the analysis are as follows. A linear
2-compartment model was found to best characterize the pooled
dexmedetomidine concentration data collected from pediatric
subjects enrolled in three studies after a range of dexmedetomidine
doses were administered as a short intravenous infusion, followed
by a maintenance infusion of varying duration. Fixed allometric
functions were used to account for the influence of body weight on
all pharmacokinetic parameters in this pediatric population. The
allometric exponent for dexmedetomidine clearance was additionally
adjusted in neonate subjects. The intercompartmental clearance and
the volume of the peripheral compartment for dexmedetomidine were
both found to be related to maturation, as described by age,
according to a power function (both decrease with increasing
age).
[0458] The effects of ethnicity, gender, alanine aminotransferase,
total bilirubin, heart physiology (single-versus double-ventricle),
use of concomitant glucuronidation pathway inhibitors, albumin
infusion, use of cardio-pulmonary bypass, and site of sampling were
not identified as statistically significant predictors of
dexmedetomidine pharmacokinetic variability.
[0459] Clearance estimates from this model increase with increasing
age and weight-adjusted clearance estimates decrease with
increasing age, approaching values expected in adults. Volume of
distribution estimates from this model increase with increasing age
and weight-adjusted volume of distribution estimates decrease with
increasing age, approaching values expected in adults. The model
evaluation supports the robustness of the model to predict well
over the entire range of concentrations.
Example 7: Pharmacokinetics of Dexmedetomidine in Pediatric
Patients Aged 12
[0460] Months to 24 Months
[0461] A 5-subject, randomized, open-label, single-center study of
dexmedetomidine was conducted on subjects aged 12 months to weeks
to <24 months of age. The study population consisted of
initially intubated and mechanically ventilated pediatric subjects
that required sedation in an intensive care setting for a minimum
of 6 hours but did not exceed 24 hours.
[0462] Subjects were randomized into one of two dose levels: dose
level 1 consisted of a 0.7 .mu.g/kg loading dose immediately
followed by a 0.5 .mu.g/kg/hr maintenance infusion; dose level 2
consisted of a 1 .mu.g/kg loading dose immediately followed by a
0.75 .mu.g/kg/hr maintenance infusion. A total of five subjects
were randomized at one site in the United States. Two subjects were
randomized to dose level 1 and three subjects to dose level 2. All
five subjects who were enrolled in the trial received
dexmedetomidine and completed the treatment. No subjects
prematurely discontinued the study.
[0463] The dose levels are outlined in Table 54 below.
TABLE-US-00056 TABLE 54 Dosing Levels Loading Maintenance Dose Dose
Dose (.mu.g/kg/hr, as a continuous Level (.mu.g/kg) infusion) 1 0.7
0.5 2 1 0.75
[0464] The dexmedetomidine was administered as a 10-minute loading
dose infusion of dexmedetomidine immediately followed by a
continuous fixed maintenance dose infusion of dexmedetomidine
across two dose levels so that the duration of infusion was a
minimum of 6 and up to 24 hours post-operatively (loading
dose+maintenance dose combined).
[0465] Dexmedetomidine was administered at the site of insertion of
the IV catheter to avoid flushing the drug. No other medications
were to be administered through the IV line designated for
dexmedetomidine..sup.a
[0466] The dexmedetomidine administered was Precedex.RTM.
(dexmedetomidine hydrochloric acid injection, 100 .mu.g/mL, base).
The dexmedetomidine solution was diluted to 4 .mu.g/mL in 0.9%
sodium chloride or dextrose 5% in water. The dexmedetomidine
solution was not to be refrigerated.
[0467] A subject was allowed to be extubated at any time after
dexmedetomidine administration began. The dexmedetomidine was
infused using a controlled infusion device. Manually controlled
microdrippers, macrodrippers, or other nonautomated infusion
devices were not permitted. Dexmedetomidine could not be given as a
bolus dose. In order to ensure proper infusion, dexmedetomidine was
not administered directly into the pulmonary artery.
[0468] The level of sedation was assessed using the University of
Michigan Sedation Scale. Pain was assessed using the Faces, Legs,
Activity, Cry and Consolability (FLACC) scale. Following completion
of screening procedures, the dexmedetomidine infusion began after
discontinuation of all other sedative agents and after the subject
had attained a UMSS.ltoreq.4. Sedation dosages were calculated
using the subject's most recently measured weight (considered
baseline weight).
[0469] Subjects who remained intubated or were reintubated during
the post-infusion period or required sedation for other reasons
during the post-infusion period were treated according to standard
of care at the study site. However, this did not include
dexmedetomidine until all post-infusion pharmacokinetics samples
had been obtained. When applicable, open-label dexmedetomidine
could resume 24 hours from study drug discontinuation.
[0470] For subjects to be considered evaluable, they must have
received at least 5 hours of continuous dexmedetomidine
administration. The dexmedetomidine infusion could not have
extended beyond 24 hours. Once dexmedetomidine was discontinued (no
weaning of dexmedetomidine allowed), post-infusion procedures began
and continued for 24 hours. During the dexmedetomidine
administration period, the dexmedetomidine infusion rate could not
be titrated.
[0471] A schematic of the overall study design is provided below in
Table 55 below.
[0472] Adequacy of sedation was assessed using the UMSS throughout
the study, with the target level of sedation a UMSS score between 2
and 4. Prior to the start of dexmedetomidine infusion, a baseline
score using the UMSS was obtained. The UMSS score was measured
according to the following schedule: just prior to loading dose,
and then at 5 and 10 minutes during loading dose; at the start of
maintenance of infusion, and at 5, 10, 15, 30, and 60 minutes for
the first hour; every 4 hours thereafter during the remainder of
the maintenance infusion; and within 5 minutes of obtaining each
pharmacokinetics sample.
[0473] If a subject was not at the desired target level of sedation
(i.e., UMSS<2), rescue medication could be administered for
sedation. The rescue medication was midazolam. Repeated rescue with
midazolam (0.05 to 0.1 mg/kg) at a recommended frequency of every 2
to 3 minutes per dose or at a frequency based on investigator
judgment could be provided until the subject had reached the
desired sedation level. A UMSS was obtained within 5 minutes prior
to and within 5 minutes following administration of rescue
midazolam along with the dose of rescue midazolam administered.
[0474] Pain was assessed using the FLACC scale. Rescue opiate
analgesia, consisting of IV fentanyl was administered, based on the
judgment of the investigator, or when the FLACC score was >4.
The fentanyl was administered either as an intermittent bolus or as
a continuous IV infusion.
[0475] If fentanyl was given as a bolus, a FLACC score was recorded
within 5 minutes prior to and within 5 minutes following fentanyl
bolus administration together along with the dose of rescue
fentanyl administered. If fentanyl was given as a continuous
infusion, FLACC scores were obtained with the scheduled vital signs
every 4 hours. If the infusion was titrated, pain assessments were
collected within 5 minutes prior to and within 5 minutes following
each titration. The recommended dosage for fentanyl administration
was an IV bolus of 1 to 4 .mu.g/kg/dose every 2 to 4 hours as
needed and a continuous IV infusion of 1 to 3 .mu.g/kg/hr.
[0476] Following the discontinuation of dexmedetomidine, further
sedation and analgesia were allowed to be provided per standard of
care; however, dexmedetomidine could not be restarted until after
completion of the 24-hour post-dexmedetomidine observation
period.
[0477] Midazolam or fentanyl was used in instances where severe
anxiety/agitation or pain was anticipated (e.g., prior to a painful
procedure, such as suctioning or chest tube removal). The date,
time, and type of any painful procedure (e.g., suctioning, chest
tube removal) were recorded. In addition, the date and time of any
non-pharmacologic intervention (e.g., swaddling, cuddling, and
rocking) were documented, and a UMSS and/or FLACC score were
recorded within 5 minutes prior to and within 5 minutes following
the intervention.
[0478] At any time clinically indicated (e.g., subject discomfort
despite maximum doses of rescue), or at the discretion of the
investigator, the subject could have been converted to an
alternative sedative or analgesic therapy that was not permitted
within this protocol. This did not occur in this study.
[0479] Thirteen (13) 1 mL venous blood samples (.about.1/2 tsp)
were collected via a peripheral venous, central venous, or
peripherally-inserted central catheter line into heparinized vacuum
tubes at each of the following time points for pharmacokinetics
analysis: no more than 30 minutes prior to start of the loading
dose; within 5 minutes before finishing the loading dose; 30
minutes, 1, 2, and 4-6 hours after start of maintenance infusion;
within 30 minutes prior to end of maintenance infusion (must be
within 24 hours of start of maintenance infusion); 10 minutes after
end of maintenance infusion; and 30 minutes, 1, 2, 4, and 10 hours
after end of maintenance infusion.
[0480] For pharmacokinetics analyses, venous blood samples (1 mL)
were collected in heparinized tubes at a site opposite from the
site of infusion (e.g., left arm versus right arm). Samples were
not drawn from the second lumen of a multilumen catheter through
which dexmedetomidine was being administered.
[0481] The pharmacodynamics measurements were conducted no more
than 5 minutes prior to the scheduled blood draws. Pharmacodynamic
measurements included: sedation scores from UMSS; pain scores from
FLACC; use of rescue medication (midazolam or fentanyl); and vital
signs, i.e., HR, SBP, DBP, mean arterial pressure, respiratory
rate, and oxygen saturation by pulse oximetry.
[0482] An adverse event was defined as any untoward medical
occurrence associated with the use of a drug in humans, whether or
not considered drug-related. An adverse event could therefore be
any unfavorable and unintended sign (e.g., an abnormal laboratory
finding), symptom, or disease temporally-associated with the use of
a medicinal (investigational) product, whether or not the event was
considered causally-related to the use of the product.
[0483] Such an event can result from use of the drug as stipulated
in the protocol or labeling, from any use of the drug (e.g.,
off-label, use in combination with another drug) and from any route
of administration, formulation, or dose as well as from accidental
or intentional overdose, drug abuse, or drug withdrawal. Any
worsening of a pre-existing condition or illness was considered an
adverse event. Clinically significant abnormalities were to be
followed to resolution (i.e., become stable, return to normal,
return to baseline, or become explainable). Laboratory
abnormalities and changes in vital signs were considered adverse
events only if they resulted in discontinuation from the study,
necessitated therapeutic medical intervention, met
protocol-specific criteria, and/or if the Investigator considered
them to be adverse events.
[0484] An elective surgery/procedure scheduled to occur during the
study was not considered an adverse event if the surgery/procedure
was performed for a pre-existing condition and the
surgery/procedure had been planned prior to study entry. However,
if the pre-existing condition deteriorated unexpectedly during the
study (i.e., surgery performed earlier than planned), then the
deterioration of the condition for which the elective
surgery/procedure was being done was to be considered an adverse
event.
[0485] Common post-operative sequelae specifically related to
surgery were not reported as adverse events. The following sequelae
at the surgical wound site were considered common
surgically-related events and were not reported as adverse events:
bleeding, bruising, itching, redness, swelling, numbness, tingling,
burning, pain, infection, and wound dehiscence.
[0486] For the period immediately following discontinuation of
dexmedetomidine and up to 7 days following the start of
dexmedetomidine or hospital discharge (whichever came first),
subjects were followed for the onset of adverse events. Special
attention was made to follow the adverse events including but not
limited to rebound tachycardia or hypertension, signs of
withdrawal, agitation/rage, and pulmonary system complications
(i.e., acute respiratory distress syndrome). The occurrence of
comorbidities of prematurity, such as intraventricular hemorrhage,
necrotizing enterocolitis, sepsis and persistent ductus arteriosus
were also assessed. No serious adverse events occurred during this
study.
[0487] All non-serious adverse events that occurred from the start
of dexmedetomidine administration until 7 days following the start
of dexmedetomidine were collected, whether elicited or
spontaneously reported by the subject. In addition, serious adverse
events were collected from the time the subject's legal
representative signed the study-specific informed consent form
until 7 days following the start of dexmedetomidine
administration.
[0488] Laboratory evaluations were drawn at three time points:
pre-dose; 4 to 6 hours after start of maintenance infusion; and 10
hours after end of maintenance infusion. All blood samples were
collected in appropriately labeled tubes and sent for analysis.
Whenever possible, in order to avoid extra blood draws, the
laboratory blood samples were drawn simultaneously with 1 of the
scheduled pharmacokinetics samples. The clinical laboratory tests
performed are given in Table 56 below.
TABLE-US-00057 TABLE 56 Clinical Laboratory Tests Hematology Blood
Chemistry Urinalysis Hematocrit Blood Urea Nitrogen (BUN) Specific
gravity Hemoglobin Creatinine Ketones Red blood cell (RBC) count
Total bilirubin pH White blood cell (WBC) Serum glutamic-pyruvic
Protein count transaminase (SGPT/ALT) Blood Neutrophils Serum
glutamic-oxaloacetic Glucose Bands transaminase (SGOT/AST)
Lymphocytes Alkaline phosphatase Monocytes Sodium Basophils
Potassium Eosinophils Magnesium Platelet count (estimate Calcium
not acceptable) Phosphorus Uric acid Total protein Glucose
Albumin
[0489] Core body temperature (i.e., tympanic, rectal, or via
indwelling device) was monitored. Abnormal body temperatures were
to be recorded as adverse events according to the clinical judgment
of the investigator. Subjects with body temperature fluctuations
below 35.6.degree. C. (96.degree. F.) or above 38.6.degree. C.
(101.5.degree. F.) were evaluated for the presence of an adverse
event.
[0490] A physical examination was performed during the screening
period to establish baseline values for evaluations and in close
proximity to 24 hours after the discontinuation of the
dexmedetomidine infusion or on the day of discharge, whichever came
first. All input/output fluid volumes were captured during the
dexmedetomidine infusion period.
[0491] Electrocardiograms were obtained at the following times:
pre-dose; 4 to 6 hours after start of maintenance infusion; and 10
hours after end of maintenance infusion. A clinically significant
abnormality was grounds for excluding a subject from entry into the
study. All subjects underwent continuous cardiac monitoring
throughout the dexmedetomidine infusion period. The interpretation
of the ECG was recorded as either normal, abnormal not clinically
significant, or abnormal clinically significant by the investigator
or physician.
[0492] Pharmacokinetic assessments of clearance, exposure,
distribution, and elimination were appropriate for this study. The
pharmacodynamic assessments using the UMSS (sedation) and FLACC
(pain) have been established as validated and reliable. The safety
measures used in this study were considered standard and
suitable.
[0493] The primary evaluation was the assessment of dexmedetomidine
pharmacokinetics. Data from all fully evaluable subjects (i.e.,
those receiving at least 5 hours of dexmedetomidine infusion) were
included in the analyses. Pharmacodynamic measurements were
conducted within 5 minutes prior to scheduled blood draws. Standard
pharmacokinetics parameters were estimated by non-compartmental
methods and/or population pharmacokinetics methods. Parameters of
dexmedetomidine that were calculated included: area under the
concentration-time curve; observed peak plasma concentration;
steady state concentration; plasma clearance; terminal-phase
elimination rate constant; observed time to reach maximum plasma
concentration, expressed in hours; terminal elimination half-life;
volume of distribution; and volume of distribution at steady state.
Additional parameters, including pharmacokinetics parameters
adjusted for weight and/or dose may have been determined as deemed
appropriate (e.g., plasma clearance, weight adjusted
[CL.sub.w]).
[0494] Pharmacodynamic variables included: sedation scores from
UMSS; pain scores from FLACC; use of rescue medication (midazolam
or fentanyl); and vital signs, i.e., SBP, DBP, MAP, HR, RR,
SpO.sub.2.
[0495] Analysis of safety variables were based on the incidence of
adverse events, clinical laboratory tests, changes from
screening/baseline in vital signs, ECGs, and input/output fluid
balance. The following variables were also assessed: use of rescue
regimens to support vital signs, use of concomitant medications,
and incidence of signs of withdrawal (changes in blood pressure or
HR) after discontinuing dexmedetomidine infusion.
[0496] The statistical analyses were performed using SAS, version
9.1. For continuous variables, N, mean, median, standard deviation
(SD), minimum, Q1, Q3, and maximum are presented. The mean and
median are displayed to 1 decimal place more than the raw value.
The SD is displayed to 2 decimal places more than the raw value.
For categorical variables, N and percent are shown. All percentages
are reported to 1 decimal place.
[0497] Descriptive statistics (N, mean, SD, median, min, Q1, Q3,
max, and CV [%]) were used to summarize the pharmacokinetics
parameters for each of the dose groups, and where
pharmacokinetically appropriate, across all dose groups. Standard
pharmacokinetics parameters were estimated by non-compartmental
methods and/or population pharmacokinetics methods. Normalization
of parameters based on administered dose could have been done as
appropriate.
[0498] The following pharmacodynamic variables were evaluated: the
percentage of subjects that required rescue midazolam for sedation
during dexmedetomidine infusion; the incidence of rescue medication
use for analgesia during dexmedetomidine infusion; the (a) total
amount and (b) the weight adjusted total amount (per kg) of rescue
medication midazolam or fentanyl given for sedation and analgesia
during dexmedetomidine infusion; the time to first dose of rescue
medication for sedation and analgesia were summarized with Kaplan
Meier estimates; the absolute time and percentage of time on
dexmedetomidine infusion that the subject had UMSS 2-4 and
UMSS<2 was summarized for each dose level with descriptive
statistics; descriptive statistics for FLACC scores while on study
drug were summarized using all FLACC scores for a subject; and the
time to successful extubation in subjects was summarized with
Kaplan-Meier estimates.
[0499] The time on dexmedetomidine was summarized descriptively for
each dose level, and also the number and percentage of subjects
exposed to dexmedetomidine during the treatment period was
summarized (N and percent) by time of exposure for the following
time periods (<6 hour, <12 hour, <24 hours) and
(>0-<6 hours, 6-<12 hours, 12-<24 hours, and 24 hours)
by dose level.
[0500] Loading dose was summarized using the parameters total dose
and duration of dose. Maintenance dose was summarized descriptively
for each dose level and age group by total dose infused (m/kg),
average dose (m/kg/hr), and duration of hours dosed. Total dose
infused equaled infusion rate (m/kg/hr) times duration of infusion
(hour). The total dose of dexmedetomidine infused (m/kg), total
dose (m), and the length of infusion (hours) was summarized
descriptively by dose level.
[0501] Prior and concomitant medications were summarized according
to the WHO DRUG Dictionary. The number and percentage of subjects
who used prior medications (by preferred term) were tabulated for
each dose level. The number and percentage of subjects who used
concomitant medications were similarly tabulated.
[0502] Only treatment-emergent adverse events were analyzed. The
number and percentage of subjects with treatment-emergent adverse
events was summarized for each dose level according to the Medical
Dictionary for Regulatory Activities (MedDRA) system organ class
(SOC) and preferred term. Category of adverse event severity and
category of adverse event relationship to dexmedetomidine were
similarly summarized. For each subject with multiple adverse
events, only the most severe category and the closest relationship
to dexmedetomidine were counted once.
[0503] Additionally, separate tabulations were created for
treatment-emergent serious adverse events, treatment-emergent
adverse events leading to discontinuation, treatment-emergent
adverse events related to dexmedetomidine, and treatment-emergent
adverse events by severity.
[0504] For summaries by severity, if a subject had multiple events
occurring in the same SOC or same preferred term, the event with
the highest severity was summarized. Any adverse event with a
missing severity was to be summarized as severe. Relationship to
dexmedetomidine was summarized as follows: elated (included
definitely related, probably related, and possibly related) or not
related (included probably not related and not related).
[0505] All laboratory values outside the normal range were flagged
in the data listings and clinically significant abnormal laboratory
values were recorded. The number and percentage of subjects with
clinically significant abnormal laboratory values at the baseline,
during dexmedetomidine infusion, and during the
post-dexmedetomidine period were summarized for each age group
overall and by dose level. Descriptive statistics for clinical
laboratory tests and change from baseline were summarized.
[0506] The mean, minimum, and maximum of the post-baseline vital
signs HR, SBP, DBP, MAP, RR, and SpO.sub.2.measured during the
dexmedetomidine infusion period and during the 24-hour follow-up
were determined for each subject. The absolute value and change
from baseline was summarized descriptively for each of the mean,
minimum, and maximum value by dose level. The incidence of abnormal
ECG findings at baseline, during dexmedetomidine infusion, and
during the post-dexmedetomidine period was tabulated by dose
level.
[0507] The total amount of input (mL) and the total amount of
output (mL) measured during the dexmedetomidine infusion period and
post-dexmedetomidine infusion were calculated for each subject, and
descriptively summarized by dose level.
[0508] Two subjects received sedatives or analgesics during
dexmedetomidine infusion which were protocol violations. These were
two dose level 2 subjection, one of whom received morphine and
sufentanil for pain and the other subject received propofol for
tracheostomy tube placement. These deviations were not believed to
have had an impact on the safety of the subjects.
[0509] The most common medical history included cardiovascular and
respiratory disease in all five subjects. Four of the five subjects
had gastrointestinal conditions. All subjects were
post-surgery.
[0510] All five subjects received prior medication before entering
this study and concomitant medication during the study. The most
common prior or concomitant drug classes were categorized in the
blood and blood forming organs class (IV fluids and blood products
in particular) or drugs for the nervous system. All subjects
received at least one post-dexmedetomidine infusion medication; the
most common drugs were for the nervous system
[0511] The mean plasma pharmacokinetics parameters of
dexmedetomidine following a loading dose and a continuous
maintenance dose are given in Table 57 below.
TABLE-US-00058 TABLE 57 Mean Plasma Pharmacokinetic Parameters Dose
Level 1 Dose Level 2 DEX LD = 0.7 .mu.g/kg DEX LD = 1 .mu.g/kg
Pharmacokinetic MD = 0.5 .mu.g/kg/hr MD = 0.75 .mu.g/kg/hr
Parameter (N = 2) (N = 3) (units) Mean (% CV) Mean (% CV) CL 12.192
(78.55) 5.836 (50.30) (L/hr) CL.sub.w 1.292 (87.48) 0.617 (61.79)
(L/hr/kg) AUC (0-Infinity) 4639.170 (87.48) 14203.544 (91.89)
[(pg/mL)hr] AUC (0-Infinity).sub.Dose 118.610 (78.55) 221.131
(67.92) [(pg/mL)hr/.mu.g] C.sub.max 4499.925 (129.49) 11737.387
(30.24) (pg/mL) V.sub.d 31.845 (64.17) 15.780 (22.47) (L) V.sub.dw
3.343 (74.52) 1.590 (39.01) (L/kg) t.sub.1/2 1.958 (19.22) 2.260
(53.99) (hr) CV = coefficient of variation; LD = Loading dose; MD =
maintenance dosing
[0512] T.sub.max was generally 0.08 hrs before the end of the
loading dose, and was fairly constant across all subjects and both
dose levels. The one exception (Subject 01-0007, dose level 2) had
a T.sub.max of 0.68 hrs after the start of the maintenance
infusion.
[0513] Exposure to dexmedetomidine, measured as C.sub.max or AUC,
appeared to be dose-related, although highly variable. Mean
C.sub.max increased from 4500 pg/mL in dose level 1 to 11737 pg/mL
in dose level 2, while dose-adjusted C.sub.max was fairly constant.
Likewise, AUC (0-Infinity) increased from 4639 (pg/mL)hr in dose
level 1 to 14204 (pg/mL)hr in dose level 2, whereas dose-adjusted
AUC (0-Infinity) was fairly constant. This high variability in
exposure was mainly attributable to one outlier (Subject 01-0003,
dose level 1). Also since dose level 1 and dose level 2 contain 2
and 3 subjects, respectively, pharmacokinetics data should be
interpreted cautiously (especially in the presence of a possible
outlier).
[0514] Dexmedetomidine half-life was about 2 hrs in all subjects
and was independent of dose. With the exception of one outlier
(Subject 01-0003, dose level 1), both CL and CL.sub.w were fairly
constant across both dose levels. Clearance was about 5.7 L/hr (2.5
to 8.2 L/hr) whereas weight adjusted CL was about 0.6 L/hr/kg (0.2
to 0.9 L/hr/kg). V.sub.d was also fairly constant across both dose
levels. Again with the exclusion of one outlier (Subject 01-0003,
dose level 1), V.sub.d was about 16.2 L (13.4 to 19.9 L) whereas
weight adjusted V.sub.d was about 1.6 L/kg (0.99 to 2.23 L/kg).
[0515] The mean total amount of midazolam received was 0.50 mg
(0.06 mg/kg) in Subject 01-0003 (dose level 1) and 3.70 mg (0.42
mg/kg) in Subject 01-0001 (dose level 2) who required rescue
midazolam. The mean total amount of rescue fentanyl received was 60
.mu.g (6.62 .mu.g/kg) in 1 subject in dose level 1 (Subject
01-0003) and 49.56 .mu.g (5.50 .mu.g/kg) in 2 subjects in dose
level 2 (Subjects 01-0001 and 01-0004).
[0516] The mean total amount of midazolam received was 0.50 mg
(0.06 mg/kg) in Subject 01-0003 (dose level 1) and 3.70 mg (0.42
mg/kg) in Subject 01-0001 (dose level 2) who required rescue
midazolam. The mean total amount of rescue fentanyl received was 60
.mu.g (6.62 .mu.g/kg) in 1 subject in dose level 1 (Subject
01-0003) and 49.56 .mu.g (5.50 .mu.g/kg) in 2 subjects in dose
level 2 (Subjects 01-0001 and 01-0004).
[0517] For dose level 1, Subject 01-0003 required rescue midazolam
and fentanyl. This subject required multiple IV boluses of fentanyl
for pain beginning 1.43 hours after the start of dexmedetomidine
infusion. This subject also required one dose of rescue midazolam
at 5.27 hours after the start of dexmedetomidine infusion for
agitation/surgically related pain. Relevant ongoing medical history
included hypoplastic left heart syndrome and was post-surgery
(cardiac catheterization, left pulmonary artery stenosis with
balloon dilatation and aortopulmonary collaterals that required
coil embolization). The other dose level one subject, Subject
01-0006, did not require rescue midazolam or fentanyl. However,
this subject was on lorazepam 1 mg every 6 hours per gastric tube
for seizures and could have received chloral hydrate for agitation
as needed during dexmedetomidine infusion. It was determined the
subject did not receive chloral hydrate during dexmedetomidine
infusion. This subject was post-surgery for a recurrent rectal
prolapse with surgical repair.
[0518] For dose level 2, Subject 01-0001 required rescue midazolam
and fentanyl. Rescue midazolam was given in several doses for
agitation/surgically related pain between 1.2 to 5.57 hours after
the dexmedetomidine infusion started. Rescue fentanyl was given
between 1.62 to 6.18 hours after the start of dexmedetomidine
infusion for pain in the form of several boluses and also
continuous infusions. This subject continued to receive fentanyl
after the dexmedetomidine infusion ended. Relevant medical history
included transposition of the great arteries, pulmonary stenosis,
and ventricular septal defect and was postoperative for open heart
surgery for correction of these problems (Nikaidoh operation). This
subject also received sufentanil IV and IV morphine, both one time
each for pain during dexmedetomidine infusion which were protocol
violations.
[0519] Another dose level 2 subject, Subject 01-0004, did not
require rescue midazolam, but did require rescue fentanyl given in
the form of several boluses between 0.67 hours and 5.1 hours after
the start of dexmedetomidine infusion. This subject had a history
of congenital heart disease (congenital defect of the
aortopulmonary trunk with tracheal compression and bronchial
malacia) and was post-surgery from correction of these problems
(aorotopexy).
[0520] The third dose level 2 subject, Subject 01-0007, did not
require rescue midazolam or fentanyl but received propofol during
dexmedetomidine infusion for tracheostomy tube placement (also a
protocol violation). This subject had an ongoing medical history of
hypoplastic right lung and was tracheostomy/ventilator dependent.
The subject had an imperforated anus and was post-surgery for
colostomy and anorectoplasty and colostomy reversal.
[0521] The maintenance infusion doses of dexmedetomidine used in
this trial, 0.5 .mu.g/kg/hr (dose level 1) and 0.75 .mu.g/kg/hr
(dose level 2), were moderately effective at sedating and keeping
subjects comfortable. The use of concomitant sedatives and
analgesics confounded the interpretation of the pharmacodynamic
results.
[0522] Since the subject numbers were so small, the statistical
results for the time to first dose of rescue medication were not
statistically or clinically meaningful and are not discussed
further.
[0523] For rescue midazolam, Subject 01-0003 (dose level 1)
received rescue midazolam at 5.27 hours and Subject 01-0001 (dose
level 2) beginning at 1.2 hours after the start of dexmedetomidine
infusion. For rescue fentanyl, Subject 01-0003 (dose level 1)
received rescue fentanyl beginning at 1.43 hours, Subject 01-0001
(dose level 2) beginning at 1.62 hours, and Subject 01-0004 (dose
level 2) beginning at 0.67 hours after the start of dexmedetomidine
infusion.
[0524] The target UMSS score was between 2 to 4. For dose levels 1
and 2, the median absolute time spent in this target range was 3.6
hours (58.9% of the time) and 5.9 hours (95.1% of the time),
respectively. The median absolute time spent with a total UMSS
score<2 for dose levels 1 and 2 was 2.5 hours (41.1% of the
time) and 0.3 hours (4.9%), respectively. The results observed are
confounded by the receipt of concomitant sedative/analgesic drugs
during dexmedetomidine infusion.
[0525] One of the criteria used for judging whether to give rescue
fentanyl was if the total FLACC score was >4. The median total
FLACC score was 1.6 in dose level 1 and 4.4 in dose level 2, and
3.2 for both dose levels combined. The results observed are
confounded by the receipt of concomitant sedative/analgesic drugs
during dexmedetomidine infusion. Compared to dose level 2 subjects,
subjects in dose level 1 spent considerably less time in the target
UMSS range of 2 to 4, but had lower total FLACC scores.
[0526] Generally, trends in mean change from baseline in vital
signs were not clinically meaningful. There were no
treatment-emergent adverse events pertaining to HR, SBP, DBP, MAP,
RR, or SpO.sub.2.
[0527] Two of the five subjects were able to be extubated by the
end of the study. These subjects were Subjects 01-0006 (dose level
1), extubated at 17.7 hours from the start time of study drug, and
Subject 01-0007 (dose level 2) extubated at 26.27 hours from the
start time of study drug.
[0528] The median dose and duration of dexmedetomidine exposure is
given in Table 58 below.
TABLE-US-00059 TABLE 58 Median Dose and Duration of Dexmedetomidine
Exposure Dose Level 1 Dose Level 2 Total Median Parameter (N = 2)
(N = 3) (N = 5) Loading dose N 2 3 5 Total loading dose (.mu.g)
7.02 9.11 8.90 Duration (min) 10.0 10.0 10.0 Maintenance dose N 2 3
5 Total maintenance dose (.mu.g) 30.11 41.00 41.00 Duration (min)
360.0 360.0 360.0
[0529] Only one of the five subjects (20.0%) experienced
treatment-emergent adverse events. These events were mild pyrexia
and mild atelectasis in a dose level 2 subject; both events were
assessed as not related to dexmedetomidine. There were no
treatment-emergent serious adverse events leading to death, no
other treatment-emergent serious adverse events, and no
treatment-emergent adverse events that led to dexmedetomidine
discontinuation.
[0530] There was variability between subjects in hematology tests.
In general, no evidence of systematic change for most hematologic
variables was found. However, subjects in both dose levels had
large mean decreases in the percent of lymphocytes during and
post-dexmedetomidine administration. Subjects in both dose levels
had large mean increases in the percent of neutrophils during and
post-dexmedetomidine administration. Also, dose level 2 subjects
had larger mean decreases in platelets during dexmedetomidine
administration compared to baseline than subjects in dose level 1.
Post-dexmedetomidine administration, dose level 2 subjects had a
large mean decrease in platelets while dose level 1 subjects had a
slight mean increase in platelets.
[0531] There was variability between subjects in chemistry tests.
In general, no evidence of systematic change for most chemistry
variables was found. However, during and post-dexmedetomidine
administration, dose level 2 subjects had a large mean increase in
aspartate aminotransferase (AST) compared to baseline. Both dose
levels had large mean increases in uric acid crystals. In general,
no evidence of systematic change for these urinalysis variables was
found. No subjects had abnormal hematology, chemistry, or
urinalysis results assessed as clinically significant during or
post-dexmedetomidine administration. No abnormal clinically
significant ECG findings were present in any of the 5 study
subjects at screening or during or post-dexmedetomidine
administration. There were no treatment-emergent adverse events
pertaining to hematology, chemistry, urinalysis results, HR, SBP,
DBP, MAP, RR, or SpO.sub.2. The most common abnormal findings at
screening and post-dexmedetomidine administration were in the
cardiopulmonary system.
[0532] Dexmedetomidine was safe and well tolerated at both dose
levels. The maintenance infusion doses of dexmedetomidine used in
this trial, 0.5 .mu.g/kg/hr (dose level 1) and 0.75 .mu.g/kg/hr
(dose level 2), were moderately effective at sedating and keeping
subjects comfortable.
Example 8: Pooled Pharmacokinetic Data of Dexmedetomidine in
Pediatric Patients
[0533] A population pharmacokinetic evaluation of dexmedetomidine
in pediatric subjects was completed, as described in Example 6.
Example 6 combines the populations described in Examples 1, 3 and
5. The ages enrolled in each of the studies were 1 month to <24
months (Example 5), 2 years to <17 years (Example 3) and
.gtoreq.28 weeks gestational age to <1 month (Example 1).
[0534] In this study, an additional 11 subjects were included in
the modeling described by Example 6. The additional subjects
included 6 neonatal subjects aged.gtoreq.28 weeks gestational age
to <36 weeks gestational age group treated at the second dose
level from the additional cohort of Example 1 (0.1 .mu.g/kg
load/0.1 .mu.g/kg/hr Maintenance); and the five subjects in the age
group 12 months to <24, as described in Example 7. The model
parameters were determined as described above in Example 6. Results
of the updated model are described in FIGS. 26-33.
[0535] Population pharmacokinetic modeling was performed using the
nonlinear mixed effects modeling (NONMEM.RTM.) computer program,
Version 6.0, Level 2.0 on an Intel cluster with the Linux operating
system.
[0536] The first-order conditional estimation (FOCE) with
interaction method was used at all stages of model development. The
effects of both weight and age were included in the model
considered the base structural model, given the range of weights
and ages in this pediatric population and their likely impact on
pharmacokinetic. Evaluation of the influence of other covariates
(gender, ethnicity, cardio-pulmonary bypass use, albumin infusion,
and site of sampling on elimination clearance (CL) and volume of
the central compartment (Vc); alanine aminotransferase (ALT), total
bilirubin, concomitant glucuronidation pathway inhibitors, and
heart physiology (single versus double ventricle) on CL) was
performed using a forward selection (a=0.05 plus at least a 5%
reduction in interindividual variability (IIV) in the parameter of
interest) followed by a backward elimination (a=0.001)
procedure.
[0537] Following any necessary refinements, the adequacy of the
final model was evaluated using a simulation-based
prediction-corrected visual predictive check method. Conditional on
the final model point estimates, 1000 replicates of the analysis
dataset were simulated using NONMEM, and the 5th, 50th (median),
and 95th percentiles of the distributions of the simulated
concentrations were calculated. Prediction correction was performed
for discrete bins based on the time since the end of the infusion,
treatment group, and age category. Concordance between the
prediction interval based on the simulations and the observed data
and corresponding percentiles of the observed data was assessed
visually and numerically, by calculating the percentage of observed
data points above and below the prediction interval bounds.
[0538] The population pharmacokinetic analysis results were as
follows. The base structural model for the pooled dataset of
Example 1, Example 3, and Example 5 was a 2-compartment model with
fixed allometric exponents for weight effects on clearance and
volume parameters (0.75 for CL and inter-compartmental clearance
(Q) and 1.0 for Vc and volume of the peripheral compartment (Vp)),
an additional shift in the CL and Vc exponents for neonates, and
age effects on Q and Vp described by power functions (both decrease
with increasing age). (See Example 6).
[0539] As a result of forward selection, no additional covariate
effects were added to the model as none met the pre-specified
criteria of a statistically significant reduction in the MVOF and
at least a 5% decrease in IIV. During subsequent model refinement,
the shift in the Vc allometric exponent for neonates was found to
be non-statistically significant and was thus removed from the
model.
[0540] The final base structural pharmacokinetic model was a
2-compartment model with IIV estimated on CL, Q, Vc, and Vp using
exponential error models, fixed allometric exponents on the
clearance (0.75 for CL and Q) and volume of distribution (1.0 for
Vc and Vp) parameters, with an additional shift on the CL exponent
for neonates, age effects on Q and Vp described by power functions
(both decrease with increasing age), covariance terms for the IIVs
on CL and Vp, and the IIVs on Q and Vc, separate additive plus
constant coefficient of variation error models for Example 3 and
Example 5, and a constant coefficient of variation error model for
Example 1.
[0541] The parameter estimates for the final population
pharmacokinetic model for dexmedetomidine from the original
analysis as described in Example 6 are provided in Table 51.
[0542] All fixed effect parameters were estimated with good
precision (% SEMs<20%), with the exception of those associated
with Q, which were estimated with slightly poorer precision (% SEMs
of around 40%). Random effects were also estimated with good
precision (most % SEMs<25%, except IIV in Q with % SEM=37%).
Interindividual variability in CL, Vc, and Vp was moderate, ranging
from 35% CV to 55% CV. Unexplained IIV in Q was very high at 163%
CV. Overall, RV was the lowest in the Example 5 data (around 19%
CV) and slightly higher in the Example 3 data (26% CV), but in both
studies was considerably larger at low concentration values,
especially near the lower limit of the assay. A constant
coefficient of variation RV model was found to adequately describe
the data from Example 1, with a relatively higher estimate of 46%
CV, regardless of concentration level.
[0543] The prediction-corrected visual predictive check results
indicate that the model-based simulated concentrations were in
close agreement with the observed data from the 3 studies with 6.3%
of observations and 4.7% of observations below and above the bounds
of the 90% prediction interval, respectively. Furthermore, the
median of the simulated concentration data corresponded
consistently with the median of the observed data.
[0544] The additional cohort of Example 1, consisting of six
neonatal subjects in the .gtoreq.28 weeks gestational age to <36
weeks gestational age at the second dose level (0.1 .mu.g/kg
Load/0.1 .mu.g/kg/hr Maintenance), have been completed. The five
subjects from example 7 for age group 12 months to <24 months
have also been completed. These subjects were added to the
population pharmacokinetic model described in Example 6, and the
model parameters were determined as described above for the
original analysis (i.e., Example 6). There was very little change
in the model parameters and the resulting clearance and volume of
distribution point estimates and associated 95% confidence
intervals compared to the original analysis.
[0545] The parameter estimates for the final population
pharmacokinetic model for dexmedetomidine including the additional
11 subjects completed since the original analysis are provided in
Table 59.
TABLE-US-00060 TABLE 59 Parameter Estimates and Standard Errors
From the Dexmedetomidine Final Population Pharmacokinetic Model
(Studies Example 5, Example 3, Example 1, and Example 7) Magnitude
of Interindividual Final Parameter Variability Estimate (% CV)
Population % Final % Parameter Mean SEM Estimate SEM CL (L/h).sup.a
10.7 3.4 37.01 17.0 Proportional shift in allometric 0.531 17.2
exponent for CL for neonates.sup.a Vc (L).sup.b 8.49 10.5 53.76
20.8 Inter-compartmental CL (L/h).sup.c 63.5 23.8 161.25 23.7
Exponent for power function -0.342 27.9 effect of age on Q.sup.c Vp
(L).sup.d 14.7 7.2 51.19 20.6 Exponent for power function -0.280
10.6 effect of age on Vp.sup.d Ratio of additive to 12.3 15.0 NA NA
proportional RV: Example 5 Ratio of additive to 40.4 26.0 NA NA
proportional RV: Example 3 cov(IIV in CL, IIV in Vp) 0.145 20.8 NA
NA cov(IIV in Q, IIV in Vc) 0.796 19.6 NA NA RV Example 1.sup.e
0.189 18.6 NA NA RV Example 5.sup.f 0.0358 16.5 NA NA RV Example
3.sup.g 0.0685 20.6 NA NA RV Example 7.sup.h 0.0935 29.8 NA NA
Minimum value of the objective function = 11885.512 Abbreviations:
CL, elimination clearance; IIV, interindividual variability; NA,
not applicable; NEO, indicator variable for neonates; % CV,
coefficient of variation expressed as a percentage; % SEM, standard
error of the mean expressed as a percentage; Q, inter-compartmental
clearance; RV, residual variability; Vc, volume of the central
compartment; Vp, volume of the peripheral compartment; WTKG, weight
in kg. a Typical CL = 10.7 .times. ( WTKG 9.6 ) [ 0.75 .times. ( 1
+ 0.531 .times. NEO ) ] ##EQU00014## b Typical Vc = 8.49 .times. (
WTKG 9.6 ) ##EQU00015## c Typical Q = 63.5 .times. ( WTKG 9.6 )
0.75 .times. ( age 1.31 ) - 0.342 ##EQU00016## d Typical Vp = 14.7
.times. ( WTKG 9.6 ) .times. ( age 1.31 ) - 0.280 ##EQU00017##
.sup.eResidual variability estimate is expressed as a variance. The
corresponding % CV for RV in Example 1 is 43% CV. .sup.f Residual
variability estimate is expressed as a variance. The corresponding
% CV for RV in Example 5 ranges from 111% CV at 2.12 ng/L (one-half
the lower assay limit to 19% CV at 700 ng/L. .sup.gResidual
variability estimate is expressed as a variance. The corresponding
% CV for RV in Example 3 ranges from 75% CV at 15.12 ng/L (one-half
the lower assay limit) to 26% CV at 3000 ng/L. .sup.hResidual
variability estimate is expressed as a variance. The corresponding
% CV for RV in Example 7 is 31% CV.
[0546] Table 60 provides summary statistics for the individual
Bayesian parameter estimates and the model-predicted typical value
estimates by age group for dexmedetomidine weight-adjusted CL and
weight-adjusted volume of distribution for the original (Example 6)
and updated analyses.
TABLE-US-00061 TABLE 60 Summary Statistics for the Weight-Adjusted
Clearance and Weight-Adjusted Volume of Distribution by Age Group
Weight-Adjusted Weight-Adjusted CL (L/h/kg) V.sub.d (L/kg)
Geometric Mean Geometric Mean (95% CI as (95% CI as Percent Percent
of Geo. Mean) of Geo. Mean) Including Including Initial Additional
11 Initial Additional 11 Age Group Model Subjects Model Subjects 28
weeks GA- 0.991 0.929 5.634 5.741 <1 month (81.7-122.3)
(82.45-121.4) (79.1-126.4) (80.87-123.7) (n = 22) (n = 28) (n = 22)
(n = 28) 1 month- 1.213 1.211 3.012 3.016 <6 months (82.3-121.6)
(82.16-121.7) (82.9-120.6) (82.66-121.0) (n = 14) (n = 14) (n = 14)
(n = 14) 6 months- 1.110 1.109 2.895 2.893 <12 months
(85.1-117.3) (85.21-117.4) (84.2-118 .8) (84.17-118.8) (n = 16) (n
= 16) (n = 16) (n = 16) 12 months- 1.118 1.060 2.493 2.353 <24
months (81.2-123.0) (82.45-121.3) (78.7-127.0) (77.31-129.4) (n =
8) (n = 13) (n = 16) (n = 13) 2 y-<6 y 1.108 1.109 2.338 2.352
(90.3-110.8) (90.17-110.8) (87.8-114.0) (87.63-114.1) (n = 26) (n =
26) (n = 26) (n = 26) 6 y-<17 y 0.796 0.796 1.677 1.681
(87.3-114.4) (87.31-114.6) (83.6-119.6) (83.58-119.6) (n = 29) (n =
29) (n = 29) (n = 29) Abbreviations: CI, confidence interval; CL,
clearance; GA, gestational age; Geo., geometric; max, maximum; min,
minimum; n, number of subjects; y, years.
[0547] Tables 61 and 62 provide summary statistics for the
individual Bayesian estimates and model-predicted typical values of
dexmedetomidine clearance and weight-adjusted clearance by age
group (Table 61) and of dexmedetomidine clearance and
weight-adjusted clearance by age group estimates by age group for
dexmedetomidine volume of distribution and weight-adjusted volume
of distribution by age group (Table 62).
TABLE-US-00062 TABLE 61 Summary Statistics for the Individual
Bayesian Estimates and Model-Predicted Typical Values of
Dexmedetomidine Clearance and Weight-Adjusted Clearance by Age
Group Weight-Adjusted CL (L/h) CL (L/h/kg) Median Median Geo.
Predicted Geo. Predicted Weight (kg) Age (y) Mean Typical Mean
Typical Age Group (min, max) (min, max) (95% CI) Value (95% CI)
Value 28 weeks GA- 2.89 0.023 2.28 2.69 0.929 0.933 <1 month
(1.09, (0.005, (1.73, (0.766, (n = 28) 3.80) 0.077) 3.02) 1.128) 1
month- 5.99 0.332 6.94 7.51 1.211 1.254 <6 months (3.15, (0.099,
(5.50, (0.995, (n = 14) 7.00) 0.484) 8.74) 1.474) 6 months- 7.28
0.657 8.15 8.69 1.109 1.195 <12 months (5.10, (0.521, (7.04,
(0.945, (n = 16) 9.34) 0.896) 9.42) 1.302) 12 months- 10.10 1.491
10.76 11.12 1.060 1.101 <24 months (8.87, (0.973, (9.14, (0.874,
(n = 13) 13.50) 1.766) 12.67) 1.286) 2 y-<6 y 13.75 3.548 15.89
14.01 1.109 1.019 (n = 26) (9.98, (2.070, (14.06, (1.000, 23.59)
5.761) 17.96) 1.229) 6 y-<17 y 30.20 9.887 24.45 25.27 0.796
0.837 (n = 29) (13.60, (6.032, (19.49, (0.695, 99.00) 16.967)
30.68) 0.912) Abbreviations: CI, confidence interval; CL,
clearance; GA, gestational age; Geo., geometric; max, maximum; min,
minimum; n, number of subjects; y, years
TABLE-US-00063 TABLE 62 Summary Statistics for the Individual
Bayesian Estimates and Model- Predicted Typical Values of
Dexmedetomidine Volume of Distribution and Weight-Adjusted Volume
of Distribution by Age Group Volume of Weight-Adjusted Distribution
(L) V (L/kg) Median Median Geo. Predicted Geo. Predicted Weight
(kg) Age (y) Mean Typical Mean Typical Age Group (min, max) (min,
max) (95% CI) Value (95% CI) Value 28 weeks GA- 2.89 0.023 14.11
16.21 5.741 5.618 <1 month (1.09, (0.005, (10.95, (4.643, (n =
28) 3.80) 0.077) 18.18) 7.100) 1 month- 5.99 0.332 17.28 18.75
3.016 3.133 <6 months (3.15, (0.099, (14.83, (2.493, (n = 14)
7.00) 0.484) 20.13) 3.649) 6 months- 7.28 0.657 21.25 19.95 2.893
2.742 <12 months (5.10, (0.521, (18.23, (2.435, (n = 16) 9.34)
0.896) 24.76) 3.436) 12 months- 10.10 1.491 23.90 23.85 2.353 2.361
<24 months (8.87, (0.973, (18.66, (1.819, (n = 13) 13.50) 1.766)
30.61) 3.044) 2 y-<6 y 13.75 3.548 33.70 28.09 2.352 2.043 (n =
26) (9.98, (2.070, (29.07, (2.061, 23.59) 5.761) 39.07) 2.684) 6
y-<17 y 30.20 9.887 51.65 52.97 1.681 1.754 (n = 29) (13.60,
(6.032, (39.96, (1.405, 99.00) 16.967) 66.77) 2.011) Abbreviations:
CI, confidence interval; CL, clearance; GA, gestational age; Geo.,
geometric; max, maximum; min, minimum; n, number of subjects; y,
years
[0548] FIG. 26 and FIG. 27 provide the 95% confidence intervals for
the individual Bayesian estimates expressed as the percent of the
geometric mean of dexmedetomidine weight-adjusted CL and
weight-adjusted volume of distribution for each age group as
determined from the original analysis.
[0549] FIG. 28 and FIG. 29 provide the 95% confidence intervals for
the individual Bayesian estimates expressed as the percent of the
geometric mean of dexmedetomidine weight-adjusted CL and
weight-adjusted volume of distribution for each age group as
determined from the updated analysis.
[0550] FIGS. 30A-H show goodness-of-fit plots for the final
population pharmacokinetic model for dexmedetomidine of the present
study. FIGS. 31A-B show the prediction-corrected visual predictive
check results. Prediction interval overlaid on the observed data is
shown in FIG. 31A, and percentiles of the observed data is shown in
FIG. 31B. FIG. 32 shows the geometric means and 95% confidence
intervals for the Bayesian estimates of dexmedetomidine clearance
and weight-adjusted clearance in specified age groups with the
population model-based typical values of clearance and
weight-adjusted clearance overlaid. FIG. 33 shows the geometric
means and 95% confidence intervals for the Bayesian estimates of
dexmedetomidine volume distribution and weight-adjusted volume of
distribution in specified age groups, with the population
model-based typical values of volume of distribution and
weight-adjusted volume of distribution overlaid.
[0551] There was very little difference in the pharmacokinetic
model parameters from the original analysis and the updated
analysis which included the additional 11 subjects. The final model
fully characterizes the pharmacokinetic of dexmedetomidine in
pediatric subjects ages 28 weeks GA to <17 years. The results
for all age groups from both analyses show that the 95% confidence
intervals are completely contained within 60% and 140% of the point
estimate.
[0552] The present invention is not to be limited in scope by the
specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description and the accompanying figures. Such
modifications are intended to fall within the scope of the appended
claims.
[0553] Patents, patent applications publications product
descriptions, and protocols are cited throughout this application
the disclosures of which are incorporated herein by reference in
their entireties for all purposes.
* * * * *