U.S. patent application number 15/074716 was filed with the patent office on 2016-07-14 for methods of therapeutic monitoring of nitrogen scavenging drugs.
The applicant listed for this patent is Horizon Therapeutics, Inc.. Invention is credited to Masoud Mokhtarani, Bruce Scharschmidt.
Application Number | 20160199334 15/074716 |
Document ID | / |
Family ID | 47892277 |
Filed Date | 2016-07-14 |
United States Patent
Application |
20160199334 |
Kind Code |
A1 |
Scharschmidt; Bruce ; et
al. |
July 14, 2016 |
METHODS OF THERAPEUTIC MONITORING OF NITROGEN SCAVENGING DRUGS
Abstract
The present disclosure provides methods for evaluating daily
ammonia exposure based on a single fasting ammonia blood level
measurement, as well as methods that utilize this technique to
adjust the dosage of a nitrogen scavenging drug, determine whether
to administer a nitrogen scavenging drug, and treat nitrogen
retention disorders.
Inventors: |
Scharschmidt; Bruce; (San
Francisco, CA) ; Mokhtarani; Masoud; (Walnut Creek,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Horizon Therapeutics, Inc. |
Lake Forest |
IL |
US |
|
|
Family ID: |
47892277 |
Appl. No.: |
15/074716 |
Filed: |
March 18, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14958259 |
Dec 3, 2015 |
9326966 |
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15074716 |
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14816674 |
Aug 3, 2015 |
9254278 |
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14958259 |
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13775000 |
Feb 22, 2013 |
9095559 |
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14816674 |
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13417137 |
Mar 9, 2012 |
8404215 |
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13775000 |
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61542100 |
Sep 30, 2011 |
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61564668 |
Nov 29, 2011 |
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Current U.S.
Class: |
514/533 |
Current CPC
Class: |
A61P 1/16 20180101; A61K
31/216 20130101; G01N 2800/52 20130101; G01N 33/4925 20130101; A61P
25/00 20180101; G01N 33/84 20130101; A61P 39/02 20180101; A61P 7/00
20180101; A61P 3/00 20180101; Y10T 436/175383 20150115; G01N
2800/04 20130101; A61K 31/235 20130101; A61P 43/00 20180101; A61P
13/00 20180101; A61K 9/0053 20130101; G01N 2800/085 20130101; G01N
31/221 20130101 |
International
Class: |
A61K 31/216 20060101
A61K031/216; G01N 33/84 20060101 G01N033/84 |
Claims
1.-11. (canceled)
12. A method of treating a subject with a urea cycle disorder who
has previously been administered an initial dosage of glyceryl
tri-[4-phenylbutyrate], and who has a fasting plasma ammonia level
less than the upper limit of normal for plasma ammonia level, the
method comprising: (a) measuring a fasting plasma ammonia level for
the subject by analyzing, a plasma sample from the subject that has
been stored at 0-15.degree. C.; (b) comparing the fasting plasma
ammonia level to the upper limit of normal for plasma ammonia
level; and (c) if the fasting plasma ammonia level is greater than
half the upper limit of normal for plasma ammonia level,
administering an increased dosage of glyceryl
tri-[4-phenylbutyrate].
13. The method of claim 12, wherein the plasma sample is analyzed
within 3 hours of collection.
14. The method of claim 12, wherein the plasma sample is analyzed
within less than 1 hour of collection.
15. The method of claim 12, wherein the plasma sample is analyzed
immediately after collection.
16. The method of claim 12, further comprising repeating steps (a)
to (c) until the subject exhibits a fasting plasma ammonia level at
or below half the upper limit of normal for plasma ammonia
level.
17. The method of claim 12, wherein the upper limit of normal for
plasma ammonia level is 35 .mu.mol/L.
18. The method of claim 12, wherein the adjusted dosage of glyceryl
tri-[4-phenylbutyrate] is administered orally.
19. A method of treating a subject with a urea cycle disorder who
has previously been administered an initial dosage of glyceryl
tri-[4-phenylbutyrate], and who has a fasting plasma ammonia level
less than the upper limit of normal for plasma ammonia level, the
method comprising: (a) measuring a fasting plasma ammonia level for
the subject by analyzing a plasma sample from the subject that has
been stored at below 0.degree. C.; (b) comparing the fasting plasma
ammonia level to the upper limit of normal for plasma ammonia
level; and (c) if the fasting plasma ammonia level is greater than
half the upper limit of normal for plasma ammonia level,
administering an increased dosage of glyceryl
tri-[4-phenylbutyrate].
20. The method of claim 19, wherein the plasma sample is stored at
.ltoreq.-18.degree. C.
Description
RELATED APPLICATIONS
[0001] The present application is a divisional of U.S. patent
application Ser. No. 13/417,137, filed Mar. 9, 2012 and now
pending, which claims the benefit of U.S. Provisional Application
No. 61/564,668, filed Nov. 29, 2011, and U.S. Provisional
Application No. 61/542,100, filed Sep. 30, 2011, the disclosures of
which are incorporated by reference herein in their entirety,
including drawings.
BACKGROUND
[0002] Nitrogen retention disorders associated with elevated
ammonia levels include urea cycle disorders (UCDs) and hepatic
encephalopathy (HE).
[0003] UCDs include several inherited deficiencies of enzymes or
transporters necessary for the synthesis of urea from ammonia,
including enzymes involved in the urea cycle. The urea cycle is
depicted in FIG. 1, which also illustrates how certain
ammonia-scavenging drugs act to assist in elimination of excessive
ammonia. With reference to FIG. 1, N-acetyl glutamine synthetase
(NAGS)-derived N-acetylglutamate binds to carbamyl phosphate
synthetase (CPS), which activates CPS and results in the conversion
of ammonia and bicarbonate to carbamyl phosphate. In turn, carbamyl
phosphate reacts with ornithine to produce citrulline in a reaction
mediated by ornithine transcarbamylase (OTC). A second molecule of
waste nitrogen is incorporated into the urea cycle in the next
reaction, mediated by arginosuccinate synthetase (ASS), in which
citrulline is condensed with aspartic acid to form argininosuccinic
acid. Argininosuccinic acid is cleaved by argininosuccinic lyase
(ASL) to produce arginine and fumarate. In the final reaction of
the urea cycle, arginase (ARG) cleaves arginine to produce
ornithine and urea. Of the two atoms of nitrogen incorporated into
urea, one originates from free ammonia (NH.sub.4.sup.+) and the
other from aspartate. UCD individuals born with no meaningful
residual urea synthetic capacity typically present in the first few
days of life (neonatal presentation). Individuals with residual
function typically present later in childhood or even in adulthood,
and symptoms may be precipitated by increased dietary protein or
physiological stress (e.g., intercurrent illness).
[0004] Hepatic encephalopathy (HE) refers to a spectrum of
neurologic signs and symptoms believed to result from
hyperammonemia, which frequently occur in subjects with cirrhosis
or certain other types of liver disease. Subjects with HE typically
show altered mental status ranging from subtle changes to coma,
features similar to subjects with UCDs.
[0005] Subjects with nitrogen retention disorders whose ammonia
levels and/or symptoms are not adequately controlled by dietary
restriction of protein and/or dietary supplements are generally
treated with nitrogen scavenging agents such as sodium
phenylbutyrate (NaPBA, approved in the United States as
BUPHENYL.RTM. and in Europe as AMMONAPS.RTM.) or sodium benzoate.
These are often referred to as alternate pathway drugs because they
provide the body with an alternate pathway to urea for excretion of
waste nitrogen (Brusilow 1980; Brusilow 1991). NaPBA is a
phenylacetic acid (PAA) prodrug. Another nitrogen scavenging drug
currently in development for the treatment of nitrogen retention
disorders is glyceryl tri-[4-phenylbutyrate](HPN-100), which is
described in U.S. Pat. No. 5,968,979. HPN-100, which is commonly
referred to as GT4P or glycerol PBA, is a prodrug of PBA and a
pre-prodrug of PAA.
[0006] HPN-100 and NaPBA share the same general mechanism of
action: PBA is converted to PAA via beta oxidation, and PAA is
conjugated enzymatically with glutamine to form
phenylacetylglutamine (PAGN), which is excreted in the urine. The
structures of PBA, PAA, and PAGN are set forth below.
##STR00001##
[0007] The clinical benefit of NaPBA and HPN-100 with regard to
nitrogen retention disorders derives from the ability of PAGN to
effectively replace urea as a vehicle for waste nitrogen excretion
and/or to reduce the need for urea synthesis (Brusilow 1991;
Brusilow 1993). Because each glutamine contains two molecules of
nitrogen, the body rids itself of two waste nitrogen atoms for
every molecule of PAGN excreted in the urine. Therefore, two
equivalents of nitrogen are removed for each mole of PAA converted
to PAGN. PAGN represents the predominant terminal metabolite, and
one that is stoichiometrically related to waste nitrogen removal, a
measure of efficacy in the case of nitrogen retention states. The
difference between HPN-100 and NaPBA with respect to metabolism is
that HPN-100 is a triglyceride and requires digestion, presumably
by pancreatic lipases, to release PBA (McGuire 2010).
[0008] In contrast to NaPBA or HPN-100, sodium benzoate acts when
benzoic acid is combined enzymatically with glycine to form
hippuric acid. For each molecule of hippuric acid excreted in the
urine, the body rids itself of one waste nitrogen atom.
[0009] Methods of determining an effective dosage of PAA prodrugs
such as NaPBA or HPN-100 for a subject in need of treatment for a
nitrogen retention disorder are described in WO09/1134460 and
WO10/025303. Daily ammonia levels, however, may vary greatly in a
subject. This can lead to overestimation by the physician of the
average daily ammonia levels, which may result in overtreatment.
Thus, there is a need in the art for improved methods for PAA
prodrug dose determination and adjustment based on ammonia levels
in subjects with nitrogen retention disorders such as UCDs or
HE.
SUMMARY
[0010] Provided herein in certain embodiments are methods for
determining whether to increase a dosage of a nitrogen scavenging
drug in a subject with a nitrogen retention disorder by measuring a
fasting blood ammonia level and comparing the fasting blood ammonia
level to the upper limit of normal (ULN) for blood ammonia, where a
fasting blood ammonia level that is greater than half the ULN for
blood ammonia indicates that the dosage needs to be increased. In
certain embodiments, the nitrogen retention disorder is a UCD or
HE. In certain embodiments, the nitrogen scavenging drug is
HPN-100, PBA, NaPBA, sodium benzoate, or any combination thereof
(i.e., any combination of two or more of HPN-100, PBA, NaPBA). In
certain embodiments, the ULN is around 35 .mu.mol/L or 59 .mu.g/mL.
In certain embodiments, the methods include an additional step of
administering an increased dosage of the nitrogen scavenging drug
if the need exists, and in certain of these embodiments
administration of the nitrogen scavenging drug produces a normal
average daily ammonia level in the subject. In certain embodiments
wherein a determination is made to administer an increased dosage
of nitrogen scavenging drug and wherein the nitrogen scavenging
drug is a PAA prodrug, the methods include an additional step of
measuring urinary PAGN excretion and determining an effective
dosage of the PAA prodrug based on a mean conversion of PAA prodrug
to urinary PAGN of 60-75%.
[0011] Provided herein in certain embodiments are methods for
determining whether to administer a nitrogen scavenging drug to a
subject with a nitrogen retention disorder by measuring a fasting
blood ammonia level and comparing the fasting blood ammonia level
to the ULN for blood ammonia, where a fasting blood ammonia level
that is greater than half the ULN for blood ammonia indicates that
the nitrogen scavenging drug needs to be administered. In certain
embodiments, the nitrogen retention disorder is a UCD or HE. In
certain embodiments, the nitrogen scavenging drug is HPN-100, PBA,
NaPBA, sodium benzoate, or any combination thereof (i.e., any
combination of two or more of HPN-100, PBA, NaPBA). In certain
embodiments, the ULN is around 35 .mu.mol/L or 59 .mu.g/mL. In
certain embodiments, the methods include an additional step of
administering a nitrogen scavenging drug if the need exists, and in
certain of these embodiments administration of the nitrogen
scavenging drug produces a normal average daily ammonia level in
the subject. In certain embodiments wherein a determination is made
to administer a nitrogen scavenging drug and wherein the nitrogen
scavenging drug is a PAA prodrug, the methods further include a
step of determining an effective initial dosage of the PAA prodrug
by determining a target urinary PAGN output based on a target
nitrogen output and calculating an effective initial dosage that
results in the target urinary PAGN output based on a mean
conversion of PAA prodrug to urinary PAGN of 60-75%. In certain
embodiments, the methods include a step of administering the
calculated effective initial dosage.
[0012] Provided herein in certain embodiments are methods for
treating a nitrogen retention disorder in a subject who has
previously been administered a nitrogen scavenging drug by
measuring a fasting blood ammonia level, comparing the fasting
blood ammonia level to the ULN for blood ammonia, and administering
an increased dosage of the nitrogen scavenging drug if the fasting
ammonia level is greater than half the ULN for blood ammonia. In
certain embodiments, administration of an increased dosage of the
nitrogen scavenging drug produces a normal average daily ammonia
level in the subject. In certain embodiments, the nitrogen
retention disorder is a UCD or HE. In certain embodiments, the
nitrogen scavenging drug is HPN-100, PBA, NaPBA, sodium benzoate,
or any combination thereof (i.e., any combination of two or more of
HPN-100, PBA, NaPBA). In certain embodiments, the ULN is around 35
.mu.mol/L or 59 .mu.g/mL. In certain embodiments wherein the
nitrogen scavenging drug is a PAA prodrug, the methods include an
additional step of measuring urinary PAGN excretion and determining
an effective dosage of the PAA prodrug based on a mean conversion
of PAA prodrug to urinary PAGN of 60-75%. In certain embodiments,
the methods include a step of administering the calculated
effective dosage.
BRIEF DESCRIPTION OF DRAWINGS
[0013] FIG. 1: The urea cycle and how certain nitrogen-scavenging
drugs may assist in elimination of excessive ammonia.
[0014] FIG. 2: Relationship between fasting ammonia and average
ammonia UCD patients.
[0015] FIG. 3: Venous blood ammonia values over 24 hours in (A)
adult and (B) pediatric UCD patients.
DETAILED DESCRIPTION
[0016] The following description of the invention is merely
intended to illustrate various embodiments of the invention. As
such, the specific modifications discussed are not to be construed
as limitations on the scope of the invention. It will be apparent
to one skilled in the art that various equivalents, changes, and
modifications may be made without departing from the scope of the
invention, and it is understood that such equivalent embodiments
are to be included herein.
[0017] In subjects with a nitrogen retention disorder, the desired
effect of treatment with a nitrogen scavenging drug is control of
blood ammonia level. Control of blood ammonia level generally
refers to ammonia values within the normal range and avoidance of
hyperammonemic crises, which are often defined in the art as
transient ammonia values exceeding 100 .mu.mol/L or 178 .mu.g/mL
accompanied by clinical signs and symptoms of hyperammonemia.
Dosing of nitrogen scavenging drugs is usually based upon clinical
assessment and measurement of ammonia. However, assessment of
treatment effect and interpretation of ammonia levels is confounded
by the fact that individual ammonia values vary several-fold over
the course of a day and are impacted by timing of the blood draw in
relation to the last meal and dose of drug (see, e.g., Lee 2010;
Lichter-Konecki 2011; Diaz 2011).
[0018] A random ammonia value obtained during an outpatient visit
may fail to provide a reliable measure of a subject's status and
the drug effect. For example, basing treatment on a blood sample
taken after eating a meal might overestimate average daily ammonia
level and result in overtreatment. Conversely, basing treatment on
a blood sample taken after drug administration might underestimate
average daily ammonia level and result in undertreatment. A fasting
ammonia level at or near the ULN might be taken as an indication of
satisfactory control without appreciating the fact that the ammonia
burden during the day (average and/or highest possible value) might
be significantly higher. Thus, a fasting level at or near the ULN
may actually reflect undertreatment in a subject already a
receiving nitrogen scavenging drug or the need for treatment in a
subject not currently prescribed a nitrogen scavenging drug. A more
accurate view of daily ammonia level could be obtained by multiple
blood draws in a controlled setting over an extended period of
time. Although this is currently done in clinical trials, it is
clinically impractical.
[0019] As set forth below, the relationship between fasting ammonia
levels and daily ammonia exposure was evaluated in subjects with
nitrogen retention disorders. It was found that fasting ammonia
correlates strongly with daily ammonia exposure, assessed as a 24
hour area under the curve for ammonia, daily average, or maximal
daily concentration, and that a target fasting value which does not
exceed half of the ULN is a clinically useful and practical
predictor of ammonia values over 24 hours. As such, provided herein
are clinically practical methods of evaluating ammonia exposure in
subjects with nitrogen retention disorders based on fasting ammonia
levels, as well as methods of using the resultant information to
adjust the dosage of a nitrogen scavenging drug, determine whether
to administer a nitrogen scavenging drug, treat a nitrogen
retention disorder, and predict daily ammonia burden. The use of
fasting ammonia levels to predict ammonia exposure provides a
significant advantage over previously developed methods by reducing
the number of required blood draws and eliminating the confusion
associated with conflicting ammonia levels over the course of the
day.
[0020] As further disclosed herein, the relationship between
ammonia control and neurocognitive outcome was evaluated in UCD
patients. Previous research has demonstrated that UCD patients
often exhibit lower IQ overall and deficient executive function
manifested by difficulty in goal setting, planning, monitoring
progress and purposeful problem solving. As set forth herein, it
was found that ammonia control with GPB resulted in a significant
improvement in executive functions in pediatric patients. Based on
these results, methods are provided herein for improving executive
function in a pediatric subject with a UCD by administering one or
more nitrogen scavenging drugs.
[0021] As further disclosed herein, the relationship between
elevated PAA levels and neurological adverse events (AEs) was
analyzed. Many of the over 30 reports of administration of NaPBA
and/or sodium PAA to humans describe AEs, particularly when
administered intravenously. IV administration of PAA to cancer
patients was shown previously to result in AEs that included
fatigue, dizziness, dysgeusia, headache, somnolence,
lightheadedness, pedal edema, nausea, vomiting, and rash (Thibault
1994; Thibault 1995). These AEs correlated with PAA levels from 499
to 1285 .mu.g/mL. Although NaPBA has been used in UCD treatment for
over two decades and AEs reportedly associated with PAA are similar
to those associated with hyperammonemia, little was known
previously about the relationship between PAA levels and
neurological AEs in UCD patients. As shown herein, increased PAA
levels did not correlate with increased neurological AEs in
subjects with UCD. However, PAA levels were associated with an
increase in neurological AEs in healthy subjects. Based on these
results, methods are provided herein for predicting or diagnosing
AEs in a subject by measuring PAA levels. Further provided herein
are methods of treating and/or preventing AEs in a subject with
elevated PAA levels by administering one or more nitrogen
scavenging drugs.
[0022] Provided herein are specific target values for blood ammonia
upon which an effective dosage of a nitrogen scavenging drug can be
based. In certain embodiments, an effective dosage of a nitrogen
scavenging drug may be an initial dosage, subsequent/maintenance
dosage, improved dosage, or a dosage determined in combination with
other factors. In certain embodiments, the effective dosage may be
the same as or different than the initial dosage. In other
embodiments, the effective dosage may be higher or lower than the
initial dosage. In certain embodiments, methods are provided for
adjusting the dose or regimen of a nitrogen scavenging drug to
achieve a target ammonia level that is predictive of the average
daily ammonia level and/or the highest ammonia value that the
subject is likely to experience during the day.
[0023] Using the methods herein, a subject's fasting blood ammonia
level may be used as a predictor of daily ammonia burden, average
daily ammonia level, and/or highest daily ammonia value. Whether a
subject with a nitrogen retention disorder is receiving an optimum
dosage of nitrogen scavenging drug may be determined based on
predicted daily ammonia exposure. By optimizing the therapeutic
efficacy of a nitrogen scavenging drug, the therapeutic dosage of
the nitrogen scavenging drug is adjusted so that the subject
experiences the desired nitrogen scavenging effect. In particular,
the dose is adjusted so that the subject may experience a normal
average daily ammonia level. In certain embodiments, the effective
dosage of nitrogen scavenging drug is determined by adjusting
(e.g., increasing) a dosage to achieve a fasting blood ammonia
level for a subject that is less than or equal to half the ULN for
blood ammonia.
[0024] Provided herein in certain embodiments are methods of
determining whether the dosage of a nitrogen scavenging drug needs
to be increased in a subject with a nitrogen retention disorder
comprising comparing a fasting blood ammonia level for the subject
to a ULN for blood ammonia. If the fasting blood ammonia level has
a value that greater than half the ULN, the dosage of the nitrogen
scavenging drug needs to be increased. In certain embodiments, the
methods further comprise increasing the dosage of the nitrogen
scavenging drug if the need exists, and in certain of these
embodiments the methods further comprise administering the
increased dosage. In certain of these embodiments, administration
of the increased dosage results in a normal average daily ammonia
level in the subject.
[0025] Provided herein in certain embodiments are methods of
determining whether the dosage of a nitrogen scavenging drug needs
to be increased in a subject with a nitrogen retention disorder
comprising measuring a fasting blood ammonia level for the subject
and comparing the fasting blood ammonia level to a ULN for blood
ammonia. If the fasting blood ammonia level has a value that is
greater than half the ULN, the dosage of the nitrogen scavenging
drug needs to be increased. In certain embodiments, the methods
further comprise increasing the dosage of the nitrogen scavenging
drug if the need exists, and in certain of these embodiments the
methods further comprise administering the increased dosage. In
certain of these embodiments, administration of the increased
dosage results in a normal average daily ammonia level in the
subject.
[0026] Provided herein in certain embodiments are methods of
adjusting the dosage of a nitrogen scavenging drug in a subject
with a nitrogen retention disorder comprising comparing a fasting
blood ammonia level for the subject to a ULN for blood ammonia. If
the fasting blood ammonia level has a value that is greater than
half the ULN, the dosage of the nitrogen scavenging drug is
increased, and if the dosage is less than or equal to half the ULN
the dosage of the nitrogen scavenging drug is not increased. In
certain embodiments, the methods further comprise administering the
increased dosage. In certain of these embodiments, administration
of the increased dosage results in a normal average daily ammonia
level in the subject.
[0027] Provided herein in certain embodiments are methods of
adjusting the dosage of a nitrogen scavenging drug in a subject
with a nitrogen retention disorder comprising measuring a fasting
blood ammonia level for the subject and comparing the fasting blood
ammonia level to a ULN for blood ammonia. If the fasting blood
ammonia level has a value that is greater than half the ULN, the
dosage of the nitrogen scavenging drug is increased, and if the
dosage is less than or equal to half the ULN the dosage of the
nitrogen scavenging drug is not increased. In certain embodiments,
the methods further comprise administering the increased dosage. In
certain of these embodiments, administration of the increased
dosage results in a normal average daily ammonia level in the
subject.
[0028] Provided herein in certain embodiments are methods of
adjusting the dosage of a nitrogen scavenging drug in a subject
with a nitrogen retention disorder comprising measuring a fasting
blood ammonia level for the subject and comparing the fasting blood
ammonia level to a ULN for blood ammonia. If the fasting blood
ammonia level has a value that is greater than half the ULN, the
dosage of the nitrogen scavenging drug is increased, and if the
dosage is significantly less than half the ULN, the dosage of the
nitrogen scavenging drug may be decreased. In certain embodiments,
the methods further comprise administering the adjusted dosage. In
certain of these embodiments, administration of the adjusted dosage
results in a normal average daily ammonia level in the subject.
[0029] Provided herein in certain embodiments are methods of
adjusting the dosage of a nitrogen scavenging drug in a subject
with a nitrogen retention disorder comprising administering an
initial dosage of the nitrogen scavenging drug, measuring fasting
blood ammonia level, and comparing the fasting blood ammonia level
to a ULN for blood ammonia. If the fasting blood ammonia level has
a value that is greater than half the ULN, subsequent maintenance
dosages of the nitrogen scavenging drug are adjusted to be greater
than the initial dosage. In certain embodiments, the methods
further comprise administering the increased maintenance dosage,
and in certain of these embodiments, administration of the
increased maintenance dosage results in a normal average daily
ammonia level in the subject.
[0030] Provided herein in certain embodiments are methods of
adjusting the dosage of a nitrogen scavenging drug in a subject
with a nitrogen retention disorder to achieve a fasting blood
ammonia level that is less than or equal to half the ULN for blood
ammonia comprising measuring a fasting blood ammonia level for the
subject and comparing the fasting blood ammonia level to a ULN for
blood ammonia. If the fasting blood ammonia level has a value that
is greater than half the ULN, the subject is administered an
increased dosage of the nitrogen scavenging drug. After a time
period sufficient for the drug to reach steady state (e.g., 48
hours, 48 to 72 hours, 72 hours to 1 week, 1 week to 2 weeks,
greater than 2 weeks), fasting blood ammonia level is measured
again and compared to a ULN for blood ammonia. If the fasting blood
ammonia level has a value that is greater than half the ULN, the
dosage of the nitrogen scavenging drug is increased. This process
is repeated until a fasting blood ammonia level of less than or
equal to half the ULN is obtained.
[0031] Provided herein in certain embodiments are methods for
assessing whether a subject with a nitrogen retention disorder is
more or less likely to need a dosage adjustment of a nitrogen
scavenging drug comprising measuring a fasting blood ammonia level
for the subject and comparing the fasting blood ammonia level to a
ULN for blood ammonia, wherein a fasting blood ammonia level that
is greater than half the value of ULN indicates that the subject is
more likely to need a dosage adjustment and a fasting blood ammonia
level less than or equal to half the value of ULN indicates that
the subject is less likely to need a dosage adjustment.
[0032] Provided herein in certain embodiments are methods of
determining whether to administer a nitrogen scavenging drug to a
subject with nitrogen retention disorder comprising comparing a
fasting blood ammonia level for the subject to a ULN for blood
ammonia. If the fasting blood ammonia level has a value that is
greater than half the ULN, a nitrogen scavenging drug needs to be
administered to the subject. In certain embodiments, these methods
further comprise administering the nitrogen scavenging drug. In
certain embodiments, the subject may not have been administered any
nitrogen scavenging drugs prior to the determination. In other
embodiments, the subject may have previously been administered a
nitrogen scavenging drug other than the one being evaluated. In
these embodiments, the methods provided herein can be used to
determine whether to administer a new nitrogen scavenging drug to a
subject.
[0033] Provided herein in certain embodiments are methods of
determining whether to administer a nitrogen scavenging drug to a
subject with nitrogen retention disorder comprising measuring a
fasting blood ammonia level for the subject and comparing the
fasting blood ammonia level to a ULN for blood ammonia. If the
fasting blood ammonia level has a value that is greater than half
the ULN, a nitrogen scavenging drug needs to be administered to the
subject. In certain embodiments, these methods further comprise
administering the nitrogen scavenging drug. In certain embodiments,
the subject may not have been administered any nitrogen scavenging
drugs prior to the determination. In other embodiments, the subject
may have previously been administered a nitrogen scavenging drug
other than the one being evaluated. In these embodiments, the
methods provided herein can be used to determine whether to
administer a new nitrogen scavenging drug to a subject.
[0034] Provided herein in certain embodiments are methods for
selecting a dosage of a nitrogen scavenging drug for treating a
nitrogen retention disorder in a subject based on blood ammonia
levels comprising selecting a dosage that results in a fasting
blood ammonia level that is less than or equal to half the ULN for
blood ammonia. In certain embodiments, selecting the effective
dosage is further based on diet, endogenous waste nitrogen
excretion capacity, or any combination thereof. In certain
embodiments, the methods further comprise administering the
selected dosage.
[0035] Provided herein in certain embodiments are methods of
treating a subject with a nitrogen retention disorder who has
previously been administered a nitrogen scavenging drug comprising
measuring a fasting blood ammonia level for the subject and
comparing the fasting blood ammonia level to a ULN for blood
ammonia. If the fasting blood ammonia level has a value that is
greater than half the ULN, the subject is administered an increased
dosage of the nitrogen scavenging drug. If the fasting blood
ammonia level has a value that is less than or equal to half the
ULN, the subject is administered the same dosage or a decreased
dosage of the nitrogen scavenging drug. In certain embodiments,
administration of an increased dosage results in a normal average
daily ammonia level in the subject.
[0036] Provided herein in certain embodiments are methods of
treating a subject with a nitrogen retention disorder who has
previously been administered an initial dosage of a nitrogen
scavenging drug comprising measuring a fasting blood ammonia level
for the subject and comparing the fasting blood ammonia level to a
ULN for blood ammonia. If the fasting blood ammonia level has a
value that is greater than half the ULN, the subject is
administered a maintenance dosage that is greater than the initial
dosage of the nitrogen scavenging drug. If the fasting blood
ammonia level has a value that is less than or equal to half the
ULN, the subject is administered the initial dosage or a lower
dosage. In certain embodiments, administration of an increased
maintenance dosage results in a normal average daily ammonia level
in the subject.
[0037] Provided herein in certain embodiments are methods of
treating a subject with a nitrogen retention disorder comprising
administering a nitrogen scavenging drug, then measuring a fasting
blood ammonia level for the subject at some point after drug
administration and comparing the fasting blood ammonia level to a
ULN for blood ammonia. If the fasting blood ammonia level has a
value that is greater than half the ULN, the subject is
administered an increased dosage of the nitrogen scavenging drug.
If the fasting blood ammonia level has a value that is less than or
equal to half the ULN, the subject is administered the original or
a lower dosage of the drug.
[0038] Provided herein in certain embodiments are methods of
treating a subject with a nitrogen retention disorder comprising
administering a first dosage of a nitrogen scavenging drug,
measuring a fasting blood ammonia level for the subject, and
comparing the fasting blood ammonia level to a ULN for blood
ammonia. If the fasting blood ammonia level has a value that is
greater than half the ULN, a second dosage of a nitrogen scavenging
drug that is greater than the first dosage is administered to the
subject. A fasting ammonia blood level is measured again in the
subject and compared to a ULN for blood ammonia. If the fasting
blood ammonia level has a value that is greater than half the ULN,
a third dosage of a nitrogen scavenging drug that is greater than
the second dosage is administered to the subject. This process is
repeated until the subject exhibits a fasting blood ammonia level
with a value less than or equal to half the ULN.
[0039] Provided herein in certain embodiments are methods of
monitoring the efficacy of nitrogen scavenging drug administration
in a subject with a nitrogen retention disorder who has previously
been administered a nitrogen scavenging drug comprising measuring a
fasting blood ammonia level for the subject and comparing the
fasting blood ammonia level to a ULN for blood ammonia. If the
fasting blood ammonia level has a value that is greater than half
the ULN, the previously administered dosage of the nitrogen
scavenging drug is considered inadequate to treat the nitrogen
retention disorder. If the fasting blood ammonia level has a value
that is less than or equal to half the ULN, the previously
administered dosage is considered adequate to treat the nitrogen
retention disorder. In certain embodiments where the previously
administered dosage is considered inadequate to treat the nitrogen
retention disorder, the methods provided herein further comprise
administering an increased dosage of the nitrogen scavenging
drug.
[0040] Provided herein in certain embodiments are methods for
monitoring therapy with a nitrogen scavenging drug in a subject
having a nitrogen retention disorder comprising measuring a fasting
blood ammonia level from the subject and comparing the fasting
blood ammonia level to a ULN for blood ammonia, wherein a fasting
blood ammonia level that is greater than half the ULN indicates
that the subject is more likely to need a dosage adjustment of the
nitrogen scavenging drug, and wherein a fasting blood ammonia level
less than or equal to half the ULN indicates that the subject is
less likely to need a dosage adjustment.
[0041] A nitrogen retention disorder as used herein refers to any
condition associated with elevated blood nitrogen/ammonia levels.
In certain embodiments, a nitrogen retention disorder may be a UCD.
In other embodiments, a nitrogen retention disorder may be HE.
[0042] A nitrogen scavenging drug as used herein refers to any drug
that decreases blood nitrogen and/or ammonia levels. In certain
embodiments, a nitrogen scavenging drug may remove nitrogen in the
form of PAGN, and in certain of these embodiments the nitrogen
scavenging drug may be an orally administrable drug that contains
or is metabolized to PAA. For example, a nitrogen scavenging drug
may be a PAA prodrug such as PBA or HPN-100, a pharmaceutically
acceptable salt of PBA such as NaPBA, or a pharmaceutically
acceptable ester, acid, or derivative of a PAA prodrug. In other
embodiments, a nitrogen scavenging drug may remove nitrogen via
hippuric acid. In certain of these embodiments, a nitrogen
scavenging drug may be benzoic acid, a pharmaceutically acceptable
salt of benzoic acid such as sodium benzoate, or a pharmaceutically
acceptable ester, acid, or derivative of benzoic acid.
[0043] Increasing the dosage of a nitrogen scavenging drug may
refer to increasing the amount of drug per administration (e.g., an
increase from a 3 mL dosage to a 6 mL dosage), increasing the
number of administrations of the drug (e.g., an increase from
once-a-day dosing to twice- or three-times-a-day), or any
combination thereof.
[0044] A subject that has previously been administered a nitrogen
scavenging drug may have been administered the drug for any
duration of time sufficient to reach steady state. For example, the
subject may have been administered the drug over a period of 2 to 7
days, 1 week to 2 weeks, 2 weeks to 4 weeks, 4 weeks to 8 weeks, 8
weeks to 16 weeks, or longer than 16 weeks.
[0045] In certain embodiments of the methods disclosed herein, the
fasting period for obtaining a fasting blood ammonia level is
overnight. In certain embodiments, the fasting period is 4 hours or
more, 5 hours or more, 6 hours or more, 7 hours or more, 8 hours or
more, 9 hours or more, 10 hours or more, 11 hours or more, or 12
hours or more, and in certain embodiments the fasting period is 4-8
hours, 6-8 hours, or 8-12 hours. During the fasting period, the
subject preferably does not ingest any food. In certain
embodiments, the subject may also refrain from ingesting certain
non-food substances during the fasting period. For example, in
certain embodiments the subject does not ingest any supplements
and/or nitrogen scavenging drugs during the fasting period. In
certain of these embodiments, the subject may nonetheless ingest
one or more drugs other than nitrogen scavenging drugs during the
fasting period. In certain embodiments, the subject does not ingest
any high calorie liquids during the fasting period. In certain of
these embodiments, the subject does not ingest any liquids other
than water during the fasting period. In other embodiments, the
subject may ingest small amounts of low calorie beverages, such as
tea, coffee, or diluted juices.
[0046] In certain embodiments of the methods disclosed herein,
blood samples used for measuring fasting blood ammonia levels
and/or ULN blood ammonias are venous blood samples. In certain
embodiments, a blood sample is a plasma blood sample. Any methods
known in the art may be used to obtain a plasma blood sample. For
example, blood from a subject may be drawn into a tube containing
heparin or ethylenediaminetetraacetic acid (EDTA). In certain
embodiments, the sample can be placed on ice and centrifuged to
obtain plasma within 15 minutes of collection, stored at
2-8.degree. C. (36-46.degree. F.) and analyzed within 3 hours of
collection. In other embodiments, the blood plasma sample is snap
frozen, stored at .ltoreq.-18.degree. C. (.ltoreq.0.degree. F.) and
analyzed at a later time. For example, the sample may be analyzed
at 0-12 hours, 12-24 hours, 24-48, 48-96 hours after freezing, or
within any other timeframe over which the sample has demonstrated
stability. In certain embodiments, blood samples are taken in a
laboratory or hospital setting. In certain embodiments, a single
fasting blood sample is used to measure fasting blood ammonia
level. However, in other embodiments, multiple fasting blood
samples may be obtained. In certain embodiments, a subject's blood
ammonia level may be monitored throughout the day. Further, in
certain embodiments, the methods disclosed herein comprise an
additional step of obtaining one or more blood samples from a
subject prior to or after measuring fasting blood ammonia
level.
[0047] In certain embodiments, a blood sample is analyzed
immediately after collection. In other embodiments, the blood
sample is stored for some period between collection and analysis.
In these embodiments, the sample may be stored for less than 1
hour, 1 hour to 6 hours, 1 hour to 12 hours, 1 hour to 24 hours, or
1 hour to 48 hours. In certain of these embodiments, the blood
sample is stored at a temperature between 0-15.degree. C., such as
2-8.degree. C. In other embodiments, the blood sample is stored
below 0.degree. C. or below -18.degree. C.
[0048] Measurement of ammonia levels in a fasting blood sample is
carried out using techniques known in the art. For example, ammonia
levels may be measured using a colorimetric reaction or an
enzymatic reaction. In certain embodiments, a colorimetric reaction
may involve the use of bromophenol blue as an ammonia indicator. In
these embodiments, ammonia may react with bromophenol blue to yield
a blue dye. In certain embodiments, an enzymatic reaction may
involve glutamate dehydrogenase catalyzing the reductive amination
of 2-oxoglutarate with NH.sup.4+ and NADPH to form glutamate and
NADP.sup.+. The formation of NADP.sup.+ formed is directly
proportional to the amount of ammonia present in the blood sample.
Therefore, the concentration of ammonia is measured based on a
decrease in absorbance.
[0049] In certain embodiments of the methods disclosed herein, a
subject exhibiting a fasting blood ammonia level less than or equal
to half the ULN for blood ammonia has an average likelihood within
a confidence interval that their average daily ammonia level will
remain within a normal average daily ammonia level. In certain
embodiments, the average likelihood of having a normal daily
ammonia value is 80% to 90%. In certain embodiments, one may
predict with 95% confidence that a blood ammonia level will fall
within a certain range. In certain embodiments, one can predict
with 95% confidence that a true probability of predicting normal
values based on fasting blood ammonia is between 65% and 93%. In
other embodiments, one can predict with 80% confidence that a true
probability of predicting normal values based on fasting blood
ammonia is at least 70%. In certain embodiments, the average
likelihood of predicting normal ammonia value based on fasting
blood ammonia is about 84% with 95% confidence that the true
probability is between 65% and 93%.
[0050] In certain embodiments of the methods disclosed herein, a
subject exhibiting a fasting blood ammonia level less than or equal
to half the ULN for blood ammonia has an average likelihood within
a confidence interval that their maximum daily blood ammonia level
will not exceed 1.5 times the ULN for blood ammonia. In certain of
these embodiments, the average likelihood is about 70% to 80%. In
certain embodiments, the confidence interval is a 95% confidence
interval. In certain embodiments, the average likelihood is about
75% with 95% confidence that the true probability is between 58%
and 86%.
[0051] In certain embodiments of the methods disclosed herein, a
subject exhibiting a fasting blood ammonia level less than or equal
to half the ULN for blood ammonia has an average likelihood within
a confidence interval that their maximum daily blood ammonia level
will be less than 100 .mu.mol/L. In certain of these embodiments,
the average likelihood is 90% to 98%. In certain embodiments, the
confidence interval is 95%. In certain embodiments, the average
likelihood is about 93% with 95% confidence that the true
probability is between 77% and 100%.
[0052] The maximal ammonia value refers to the maximum amount of
ammonia that may be detected in a subject following consumption of
meals, if repeated measurement of blood ammonia can be instituted
to detect such maximum value over an extended period of time. Based
on well-controlled clinical trials with repeated blood sampling
over 24 hours, the maximum blood ammonia has been observed to occur
following the third major meal of the day in the early to mid
evening hours (4-8 PM, assuming that breakfast is approximately 8
AM; see, e.g., Lee 2010; Lichter-Konecki 2011).
[0053] The ULN for blood ammonia typically represents the highest
level in the range of normal values, which may be influenced by a
variety of factors such as the assay method, types of regents,
standard reference samples used, and specifications and calibration
of equipment used to perform the measurement. In certain
embodiments of the methods disclosed herein, the ULN for blood
ammonia is determined for a subject individually. In other
embodiments, the ULN for blood ammonia may be based on measurements
obtained across a range of subjects (i.e., subjects with UCD or
with a particular subtype of UCD, subjects with HE, healthy
subjects, etc.). In certain embodiments, the ULN for blood ammonia
may represent a standard reference value disclosed in the art, such
as a mean ULN developed across a particular subset of subjects. In
other embodiments, the ULN for blood ammonia may represent a
standard measurement that has been developed by a particular entity
that performs blood draws and/or blood evaluations, such as a
particular clinical laboratory. In certain embodiments, the ULN is
a standard reference value utilized by the same entity that
measures the fasting blood ammonia level. In these embodiments, one
skilled in the art will appreciate that interpretation of average
daily ammonia in subject with a nitrogen retention disorder must be
made relative to the reference range of normal values at the
laboratory in which the ammonia was measured. Furthermore, the
units of ammonia measurement may also vary from lab to lab (e.g.,
.mu.g/mL or .mu.moI/L), emphasizing the importance of interpreting
the subject's ammonia levels relative to the ULN at the laboratory
in which the measurement was performed. In certain embodiments, the
ULN for blood ammonia may be in the range of 26-64 .mu.mol/L. In
certain of these embodiments, the ULN for blood ammonia may be in
the range of 32-38 .mu.mol/L or 34-36 .mu.mol/L, and in certain of
these embodiments the ULN for blood ammonia is 35 .mu.mol/L. In
certain embodiments, the ULN for blood ammonia may be in the range
of 50-65 .mu.g/mL. In certain of these embodiments, the ULN for
blood ammonia may be in the range of 55-63 .mu.g/mL or 57-61
.mu.g/mL, and in certain of these embodiments the ULN for blood
ammonia is 59 .mu.g/mL.
[0054] In certain embodiments, the average daily ammonia is the
average amount of ammonia an individual may experience during the
day, if serial blood sampling were performed for ammonia
measurements. In well-controlled clinical studies, it has been
established that ammonia fluctuates several fold during the day,
depending on the timing of blood draw relative to food and drug
intake. Due to these fluctuations, the timing of individual or
serial blood sampling should be controlled relative to the timing
of food and drug intake. Even serial sampling may not be enough to
capture the peaks and troughs of the fluctuating ammonia values,
unless samples are taken frequently enough. Therefore, obtaining a
simple average of several measurements may provide inadequate or
misleading information regarding the total ammonia burden a subject
may experience during the day.
[0055] Provided herein are methods to better estimate a subject's
average daily ammonia assessed as the area under the curve for
24-hr ammonia (ammonia AUC.sub.0-24 hr) obtained from adequate and
well-spaced samples over 24 hours. This ammonia AUC.sub.0-24 hr can
be further normalized for the entire actual period of sampling,
i.e., ammonia AUC.sub.0-24 hr is divided by the sampling period
(e.g., 24 hours). For example, if an AUC of 1440 .mu.mol*hr/L is
calculated using the trapezoidal rule based on 8-11 ammonia values
obtained over 24 hours, then the average daily ammonia value or
time-normalized AUC.sub.0-24 hr would be equal to 1440
.mu.mol*hr/ml divided by the sampling time of 24 hr, or 60
.mu.mol/L. If the normal reference range at the laboratory which
performed the ammonia analysis was 10-35 .mu.mol/L, then the
average daily ammonia value for this subject would be approximately
1.71 times the ULN of 35 .mu.mol/L. Similarly, if the ammonia
AUC.sub.0-24 hr was determined to be equal to 840 .mu.mol*hr/L
based on multiple, well-spaced samples over 24 hours and analyzed
at the same laboratory, and the sampling period was 24 hours, then
the time-normalized AUC.sub.0-24 hr would be 35 .mu.mol/L. This
corresponds to an average ammonia or daily ammonia burden within
the ULN. Finally, subjects with nitrogen retention disorders such
as UCDs may experience a hyperammonemic crisis, which is often
defined clinically as a blood level exceeding 100 .mu.mol/L and
clinical manifestations of hyperammonemia, which may require
intervention to prevent irreversible hard and enable recovery.
[0056] Provided herein are methods of adjusting nitrogen scavenging
drug dosage by measuring fasting blood ammonia to minimize the
likelihood a subject may experience an ammonia value (Cmax) over 24
hours that exceeds 100 .mu.mol/L. It has been found that 100
.mu.mol/L corresponds to approximately 2-3 times the ULN in most
laboratories. Previously, if a subject with a nitrogen retention
disorder such as UCD had a blood ammonia level within or slightly
above the normal reference range for the laboratory which performed
the analysis, the subject was considered to be in good clinical
control regardless of the timing of the blood draw in relation to
meals and last administration of drug dose. However, it has been
shown that a subject with a UCD who has a fasting blood ammonia
level between the ULN and 1.5 times the ULN (e.g., 35 to 52
.mu.mol/L) has an average likelihood of only 45% (with a 95%
confidence interval of 21% to 70%) that his or her average daily
ammonia is within the normal range; an average likelihood of only
35% (with a 95% confidence interval of 13% to 60%) that his or her
maximal level of ammonia during the day is less than 1.5 times the
ULN (e.g., 52 .mu.mol/L); and an average likelihood of 25% that his
or her maximal daily ammonia level exceeds 100 .mu.mol/L during the
day. Thus, after measuring a UCD subject's fasting blood ammonia,
the dosage of a nitrogen scavenging drug may be progressively
increased and/or his or her protein intake progressively decreased
until the fasting ammonia value is less than or equal to half of
the ULN for the local laboratory in which the ammonia analysis was
performed.
[0057] In certain embodiments of the methods disclosed herein, one
or more factors other than ammonia level may be taken into
consideration when evaluating nitrogen scavenging drug dosage. For
example, blood ammonia measurements may be combined with urinary
PAGN measurements in determining whether to administer a nitrogen
scavenging drug, adjusting the dosage of a nitrogen scavenging
drug, or treating a nitrogen retention disorder. US Patent
Publication No. 2010/0008859 discloses that urinary PAGN levels
correlate more closely to PBA prodrug dosage than plasma PAA, PBA,
or PAGN levels, and further discloses that PBA prodrugs are
converted to urinary PAGN with a mean efficiency of 60-75%.
Therefore, certain embodiments of the methods disclosed herein
comprise an additional step wherein urinary PAGN levels are
measured. In certain of these embodiments, calculation of an
effective dosage of nitrogen scavenging drug is based in part on a
mean 60-75% conversion of PAA prodrug to urinary PAGN. For example,
in certain embodiments the methods disclosed herein for determining
whether to administer a nitrogen scavenging drug to a subject
comprise an additional step of measuring urinary PAGN and
calculating an effective initial dosage based on a mean conversion
of PAA prodrug to urinary PAGN of 60-75%. Similarly, in certain
embodiments the methods disclosed herein for adjusting the dosage
of a nitrogen scavenging drug comprise an additional step of
measuring urinary PAGN and calculating an effective dosage based on
a mean conversion of PAA prodrug to urinary PAGN of 60-75%. In
certain of these embodiments, the effective dosage is calculated
based on a target nitrogen output. In certain embodiments, urinary
PAGN may be determined as a ratio of the concentration of urinary
PAGN to urinary creatinine. In certain embodiments, urinary PAGN is
a factor that is taken into consideration when determining whether
to administer or increase the dosage of a nitrogen scavenging drug,
i.e., urinary PAGN is evaluated in combination with ammonia level
to determine whether to administer or increase the dosage of the
drug. In other embodiments, ammonia level alone is used to
determine whether to administer or increase the dosage of a
nitrogen scavenging drug, and urinary PAGN is simply used to
calculate the initial or adjusted dosage.
[0058] One skilled in the art will recognize that a variety of
other factors may be taken into consideration when determining the
effective dosage of a nitrogen scavenging drug. For example,
factors such as diet (e.g., protein intake) and endogenous waste
nitrogen capacity (e.g., urea synthesis capacity) may be
considered.
[0059] Provided herein in certain embodiments are kits for carrying
out the methods disclosed herein. In certain embodiments, kits are
provided for determining whether to administer or adjust the dosage
of a nitrogen scavenging drug for a subject with a nitrogen
retention disorder. The kits disclosed herein may include one or
more nitrogen scavenging drugs and/or one or more reagents (e.g.,
bromophenol blue) or enzymes (e.g., glutamate dehydrogenase) to
measure blood ammonia levels in a sample. The kit may additionally
include other pigments, binders, surfactants, buffers, stabilizers,
and/or chemicals necessary to obtain a blood sample and to measure
the ammonia level in the sample. In certain embodiments, the kits
provided herein comprise instructions in a tangible medium.
[0060] One of ordinary skill in the art will recognize that the
various embodiments described herein can be combined.
[0061] The following examples are provided to better illustrate the
claimed invention and are not to be interpreted as limiting the
scope of the invention. To the extent that specific materials are
mentioned, it is merely for purposes of illustration and is not
intended to limit the invention. One skilled in the art may develop
equivalent means or reactants without the exercise of inventive
capacity and without departing from the scope of the invention. It
will be understood that many variations can be made in the
procedures herein described while still remaining within the bounds
of the present invention. It is the intention of the inventors that
such variations are included within the scope of the invention.
EXAMPLES
Example 1
Analysis of Predictability of Pharmacodynamic Ammonia Values from
Fasting Ammonia in UCD Patients
[0062] This example demonstrates the relationship between fasting
ammonia and the pharmacodynamic (PD) profile of daily ammonia in
patients receiving PAA prodrugs for UCDs. Ammonia values vary
many-fold over the course of 24 hours in UCD patients. As depicted
in FIGS. 3a and 3b, venous ammonia was measured for 24 hours
following one week of dosing with either NaPBA or glycerol
phenylbutyrate (GPB). The graphs display ammonia values as
mean.+-.SD over 24 hours, where time zero corresponds to just prior
to dosing and breakfast (i.e., fasting state). In view of this
variability in daily ammonia levels, a single measurement may not
be very informative in determining whether a UCD patient is
optimally dosed. The ability to predict the highest potential
ammonia a UCD patient may experience during the day and the average
24-hour ammonia from a single measurement such as fasting levels
has important practical implications for nitrogen scavenging drug
dosing guidelines and patient management.
[0063] Data from two Phase 2 studies and one Phase 3 study
comparing ammonia control assessed by 24-hour sampling during
steady state treatment with HPN-100 versus NaPBA in 65 UCD patients
were used for the analysis. The two Phase 2 studies include
protocols UP 1204-003 and HPN-100-005 (Lee 2010; Lichter-Konecki
2011). The Phase 3 study includes protocols from HPN-100-006 (Diaz
2011).
[0064] Ammonia values obtained from different hospital laboratories
with different normal ranges were normalized to a standard
laboratory range of 9-35 .mu.mol/L. The patient population included
a broad range of ages, UCD subtypes, and doses of drug, and is
summarized in Table 1 below.
TABLE-US-00001 TABLE 1 UCD demographics in studies UP 1204-003,
HPN-100-005, and HPN-100-006: Gender Male 18 (27.7) n (%) Female 47
(72.3) Age at screening N 65 (years) Mean (SD) 29.46 (15.764)
Median 24.00 Range 6.0-75.0 UCD diagnosis OTC deficiency 57 (87.7)
n (%) CPS1 deficiency 1 (1.5) ASS deficiency 5 (7.7) ASL deficiency
1 (1.5) Missing 1 (1.5) Duration of NaPBA N 63 treatment Mean (SD)
114.14 (90.147) (months) Median 101.00 Range 0.2-300.0 Daily dose
NaPBA N 64 Mean (SD) 14.10 (6.255) Median 13.50 Range 1.5-36.0
[0065] Exploratory Analysis:
[0066] Several PD parameters for steady-state ammonia were
explored: AUC.sub.0-24 hr, time-normalized AUC, log AUC, maximal
ammonia value over 24 hours (Cmax), and average ammonia. Data from
65 subjects from all three studies with steady-state ammonia and
fasting ammonia were used. Missing data were imputed per procedures
specified in the protocol and statistical analysis plan, except
that no imputations were made for subjects who had no PK sampling
conducted while on a given study drug.
[0067] Sample collection times of 0-hr (before first daily dose)
and 24-hours post-dose (before first daily dose of the following
day) were both evaluated as representative of fasting ammonia. No
noticeable difference in the shape or quality of the relationship
due to the choice of time point was observed.
[0068] The relationship between fasting ammonia and pharmacokinetic
profile was evaluated separately for HPN-100 and NaPBA, with no
apparent difference in the strength or magnitude of the
relationship. Therefore, all data from both HPN-100 and NaPBA
treatments were used and conclusions regarding fasting ammonia
pertain to both HPN-100 and NaPBA.
[0069] The relationships between (1) fasting ammonia and
AUC.sub.0-24 hr and (2) fasting ammonia and maximum observed
ammonia (Cmax) were visually explored for the whole population. The
effects of the following covariates were also observed: age,
weight, gender, and dietary protein intake. A positive and strong
relationship was observed between fasting ammonia and AUC.sub.0-24
hr, with increasing fasting ammonia being associated with higher
AUC.sub.0-24 hr and maximum observed ammonia (FIG. 2).
[0070] Prediction of AUC.sub.0-24 hr Through GEE Modeling:
[0071] The aim of this modeling was to predict average daily or
highest achieved ammonia based on the subject's fasting ammonia. In
order to take into account the differences in normal ranges at
different laboratories, all ammonia values were normalized to a
reference range of 9-35 .mu.mol/L, and the predictions were
referenced to the ULN rather than a fixed value.
[0072] Generalized Estimating Equations (GEE) were used to model
the predictive ability of fasting ammonia against various ammonia
PD properties. GEE methodology can be used to analyze repeated
measures of categorical data, in which the repeated measures are
assumed to be correlated (Liang 1986). The model allows for the
specification of the assumed correlation structure without the
knowledge of the magnitude of the correlation.
[0073] The 24-hour ammonia profile was divided into ordered
categories using a variety of endpoints and cutpoints as follows:
[0074] 1) AUC [0-1.0*ULN, >1.0*ULN]; [0075] 2) AUC [0-1.5*ULN,
>1.5*ULN]; [0076] 3) Cmax [0-1.0*ULN, >1.0*ULN]; [0077] 4)
Cmax [0-1.5*ULN, >1.5*ULN]; and [0078] 5) Cmax [0-100]
.mu.mol/L.
[0079] Three levels of fasting ammonia were considered in separate
models as input: [0080] 1) [0-0.5*ULN]; [0081] 2)
[>0.5*ULN-<1.0 ULN]; and [0082] 3) [>1.0*ULN-1.5*ULN].
[0083] Using Statistical Analysis Software (SAS) Proc Genmod,
generalized linear models were fit with a logit link function.
Pre-dose fasting ammonia was the only predictor variable in the
model. The repeated nature of the data (two study periods per
subject) was modeled using GEE with exchangeable correlation
matrix. ULN for fasting ammonia was set at 35 .mu.mol/L. ULN for
AUC over 24 hours was taken as 840 (35 .mu.mol/L*24 hours); i.e.,
the AUC which corresponds to an average daily ammonia less than or
equal to 35 .mu.mol/L, which was the normalized ULN among the
participating study sites and is derived by dividing the 24-hour
area under the curve by the sampling time of 24 hours. The GEE
model was bootstrap-resampled 1,000 times according to the method
outlined in Davison, A. C. & Hinkley, D. V., Bootstrap Methods
and their Application, Cambridge University Press, London (1997),
pp. 358-362. The results of these models are shown in Table 2
below.
TABLE-US-00002 TABLE 2 Summary of results from GEE model to predict
ability of fasting ammonia against various ammonia PD properties:
Bootstrap Fasting Probability of pred. error ammonia Ammonia
outcome in Bootstrap Bootstrap rate* Model # level PK outcome
category 95% c.i. 80% c.i. (%) 1 [0-0.5 AUC in 24 0.84 0.67, 0.93
0.71, 0.89 11.5 ULN] hours [0-1.0 ULN] 2 AUC in 24 Did not converge
hours [0-1.5 ULN] 3 Cmax 0.53 0.38, 0.65 0.42, 0.61 45.8 observed
[0-1.0 ULN] 4 Cmax 0.76 0.61, 0.86 0.66, 0.82 23.3 observed [0-1.5
ULN] 5 Cmax 0.93 0.78, 1.00 0.85, 0.97 5.7 observed [0-100] 6
[0-<1.0 AUC in 24 0.58 0.42, 0.73 0.48, 0.68 42.8 ULN] hours
[0-1.0 ULN] 7 AUC in 24 0.88 0.78, 0.97 0.82, 0.94 11.1 hours
[0-1.5 ULN] 8 AUC in 24 0.97 0.90, 1.00 0.93, 1.00 2.2 hours [0-2
ULN] 9 Cmax 0.21 0.11, 0.38 0.14, 0.33 20.0 observed [0-1.0 ULN] 10
Cmax 0.52 0.35, 0.66 0.42, 0.61 46.0 observed [0-1.5 ULN] 11 Cmax
0.74 0.62, 0.85 0.91, 1.00 27.2 observed [0-2.0 ULN] 12 Cmax 0.95
0.88, 1.00 0.66, 0.81 4.3 observed [0-100] 13 [>1.0-1.5 AUC in
24 0.45 0.24, 0.71 0.30, 0.63 43 ULN] hours [0-1.0 ULN] 14 AUC in
24 Did not converge hours [0-1.5 ULN] 15 AUC in 24 0.80 0.49, 0.99
0.63, 0.92 27 hours [0-2 ULN] 16 Cmax Did not converge observed
[0-1.0 ULN] 17 Cmax 0.35 0.16, 0.58 0.23, 0.51 33 observed [0-1.5
ULN] 18 Cmax Did not converge observed [0-2.0 ULN] 19 Cmax Did not
converge observed [0-100]
[0084] From Table 2 above, we can conclude that in the population
of UCD patients described in Table 1, we can be 95% confident that,
given a fasting ammonia less than or equal to half the ULN, the
true probability of having an AUC in the range [0-840] is on
average 84%, at least 67%, and as high as 93%.
[0085] Row 1 of Table 2 above suggests that a UCD patient with a
fasting ammonia of 17 .mu.mol/L as determined by a laboratory with
a normal reference range of 9-35 .mu.mol/L (i.e., a fasting ammonia
in the range [0-0.5 ULN]) has an 84% chance (with a 95% confidence
interval of 67% to 93%) of having a time normalized AUC.sub.0-24 hr
in the normal range [AUC.sub.0-24 hr of 0-840 or an average daily
ammonia of 35 .mu.mol/L], a 76% chance (with a 95% confidence
interval of 61% to 86%) of having a Cmax of less than 1.5 ULN, and
a 93% chance (with a 95% confidence interval of 78% to 100%) of
never having an ammonia of more than 100 .mu.mol/L. Therefore, this
patient would be optimally controlled and unlikely to suffer from
high ammonia during the day.
[0086] This Example shows that fasting ammonia correlates strongly
with daily ammonia exposure, assessed as a daily average or as
maximal daily concentration, and that a target fasting value which
does not exceed half of the upper level of normal for the local lab
appears to be a clinically useful as well as practical predictor of
ammonia values over 24 hours as well. Furthermore, this Example
shows that a subject with a fasting ammonia in the range 0-0.5 ULN
has an 84% chance of having an AUC.sub.0-24 hr in the normal range
(0-840 or an average daily ammonia of 35 .mu.mol/L).
Example 2
Selecting and Adjusting HPN-100 Dosage Based on Fasting Blood
Ammonia Levels in a Patient with UCD
[0087] Patient A is an adult with UCD being managed with amino acid
supplements and dietary protein restriction only. Patient A
consumes neither his supplements nor food for approximately 8 hours
prior to a fasting morning blood draw. A venous blood draw is
performed, and fasting blood ammonia level is determined to be 52
.mu.mol/L. This fasting blood ammonia level is compared to the ULN
for blood ammonia in the laboratory performing the blood draw,
which is 35 .mu.mol/L. Based on the correlation of fasting ammonia
level to average ammonia level, it is determined that Patient A's
fasting blood ammonia level of approximately 1.5 times the ULN
represents only a 45% chance on average of having an average
ammonia during the day within the normal range. Thus, the ratio of
fasting blood ammonia level to ULN for blood ammonia indicates that
Patient A will benefit from treatment with a nitrogen scavenging
drug.
[0088] The physician elects to treat Patient A with HPN-100.
Initial dosage is determined based on body surface area or as
otherwise instructed according to HPN-100 drug labeling. Patient
A's body surface area is 1.4 m.sup.2, and therefore the initial
dosage is determined to be 9 mL per day or 3 mL TID, which is
approximately 60% of the maximum allowed dosage per HPN-100 label.
Patient A is treated with 9 mL/day of HPN-100 for at least 7 days,
and returns for an additional blood draw. The fasting blood ammonia
level at this time is 33 .mu.mol/L, which is slightly below the ULN
and falls into the range of 0.5 to 1.0 times normal. Patient A's
blood ammonia level is monitored throughout the day after
administration of a 3 mL dose of HPN-100 with each meal. It is
observed that Patient A's maximum ammonia reaches 95 .mu.mol/L
after dinner with an average daily ammonia of 66 .mu.mol/L, which
is almost two times the upper normal range. Therefore, Patient A's
dosage of HPN-100 is increased by approximately one-third to 12 mL
total or 4 mL TID. Patient A returns after at least 7 days of
treatment with HPN-100. Patient A's fasting ammonia level is 15
.mu.mol/L, which is less than half of the ULN range. It is
determined that Patient A has reached satisfactory ammonia
control.
[0089] It is expected that if Patient A adheres to his prescribed
diet, his maximal daily ammonia is not expected to exceed
approximately 52 .mu.mol/L, i.e., approximately 1.5 times the ULN,
with an average likelihood of 75% with 95% confidence. The average
ammonia level during the day is expected to remain within normal
range with greater than 84% likelihood and 95% confidence.
Moreover, Patient A's maximal daily ammonia is highly unlikely to
reach 100 .mu.mol/L during the day.
Example 3
Adjusting HPN-100 Dosage Based on Fasting Blood Ammonia Levels in a
Patient with UCD
[0090] Patient B is an 11-year UCD patient receiving 24 pills of
BUPHENYL.RTM. per day, amino acid supplements, and restricted
dietary protein intake. Patient B does not consume BUPHENYL.RTM.,
supplements, or food for approximately 6 hours prior to a fasting
morning blood draw. A venous blood draw is performed, and fasting
blood ammonia level is determined to be 40 .mu.mol/L. This fasting
blood ammonia level is compared to the ULN for blood ammonia for
the laboratory performing the blood draw, which is 35 .mu.mol/L.
Based on the correlation of fasting ammonia level to average
ammonia level, it is determined that Patient B's fasting blood
ammonia level falling between 1 and 1.5 times the ULN represents a
55% chance of having an average ammonia during the day that is
greater than the normal range, and as high as a 65% chance that her
ammonia will go above 52 .mu.mol/L or 1.5 times ULN during the
day.
[0091] Based on discussion with the patient and her mother, the
physician suspects that Patient B is noncompliant with her
medication, and decides to change her to HPN-100. The initial
dosage is determined based on the amount of BUPHENYL.RTM. Patient B
was receiving, and it is determined that Patient B needs to take
10.5 mL of HPN-100 per day. Patient B is treated with 3.5 mL of
HPN-100 3 times a day for at least 7 days, and returns for
additional blood draws. Her fasting blood ammonia level at this
time is 17 .mu.mol/L, which is below the ULN and falls into the
range of 0 to 0.5 times normal. It is determined that Patient B has
reached satisfactory ammonia control.
[0092] It is expected that if Patient B adheres to her prescribed
diet, her maximal daily ammonia will not go above approximately 50
.mu.mol/L, which is less than 1.5 times the ULN. Her average
ammonia level during the day is expected with greater than 84%
average likelihood to remain within normal range. Moreover, there
is only a small chance (7%) that Patient B's maximal daily ammonia
will exceed 100 .mu.mol/L during the day.
Example 4
Selecting and Adjusting Sodium Benzoate Dosage Based on Fasting
Blood Ammonia Levels in a Patient with UCD
[0093] Patient C is an adult UCD patient who is allergic to PBA and
is therefore being managed with amino acid supplements and dietary
protein restriction only. Patient C complains of chronic headache
and frequent nausea. Patient C consumes neither his supplements nor
food for approximately 8 hours prior to a fasting morning blood
draw. A venous blood draw is performed, and fasting blood ammonia
level is determined to be 77 .mu.mol/L. This fasting blood ammonia
level is compared to the ULN for blood ammonia for the laboratory
performing the blood draw, which is 35 .mu.mol/L. Based on the
correlation of fasting ammonia level to average ammonia level, it
is determined that Patient C's fasting blood ammonia level of
approximately 2 times the ULN represents a high likelihood of
ammonia levels going over 100 .mu.mol/L during the day. Thus, the
ratio of fasting blood ammonia level to ULN for blood ammonia
indicates that Patient C will benefit from treatment with a
nitrogen scavenging drug.
[0094] The physician decides to treat Patient C with 15 g of sodium
benzoate per day since the patient is allergic to PBA. Patient C is
treated with 15 g/day of sodium benzoate for at least 7 days, and
returns for additional blood draws. Fasting blood ammonia level at
this time is 35 .mu.mol/L, which is equal to the ULN. Patient C's
dosage of sodium benzoate is increased by approximately 30% to 18
grams per day. After at least 7 days of treatment, Patient C's
fasting ammonia level is 15 .mu.mol/L, which is less than half of
the ULN. It is determined that Patient C has reached satisfactory
ammonia control.
[0095] It is expected that if Patient C adheres to his prescribed
diet and medication, his maximal daily ammonia will not exceed
approximately 52 .mu.mol/L, which is approximately 1.5 times the
ULN. His average ammonia level during the day is expected with
greater than 80% likelihood to remain within normal range.
Moreover, Patient C's maximal daily ammonia is highly unlikely to
reach 100 .mu.mol/L during the day.
Example 5
Evaluation of the Effect of Ammonia Control on Neurocognitive
Outcome
[0096] It has been shown that UCD patients are likely to suffer
from diminished intelligence and impaired neurocognitive functions
(Kirvitsky 2009). These neuropsychological impairments have been
attributed to repeated episodes of acute hyperammonemia
interspersed on chronically elevated ammonia. Abnormalities in
neuropsychological function and/or brain imaging have been detected
even in UCD patients with mild disorders who exhibit normal IQ
and/or appear clinical normal (Gropman 2008a; Gropman 2008b).
Therefore, it was hypothesized that maintaining average daily
ammonia within normal limits and thereby reducing the long term
ammonia burden could result in improved cognition.
[0097] The relationship between reducing ammonia burden by
maintaining fasting ammonia at or close to half ULN and
neuropsychological outcomes in pediatric UCD patients was explored
in clinical trials. Eleven pediatric patients ages 6-17 were
enrolled in short term switch over comparison of NaPBA and HPN-100
in controlling ammonia. These patients underwent 24-hr serial
sample collection in a confined setting where the last sample at 24
hr was considered fasting and under supervision of the study
personnel. At the end of treatment with HPN-100 the average fasting
ammonia at 24-hr time point was 15.5 .mu.mol/L or less than half
ULN, indicating good clinical control. These 11 patients along with
another 15 pediatric patients were enrolled in two long term
studies and received HPN-100 for 12 months, during which monthly
fasting ammonia were collected. At the time of enrollment and at
the end of the study, all patients underwent assessment for
neuropsychological outcomes including the following: BRIEF
(Behavior Rating Inventory of Executive Function) to assess
day-to-day executive functioning, CBCL (Child Behavior Checklist)
to evaluate internalizing (e.g., mood/anxiety) and externalizing
behaviors, and WASI (Wechsler Abbreviated Scale of Intelligence) to
estimate of intellectual ability.
[0098] During the 12 month treatment with HPN-100, pediatric UCD
patients experienced fewer episodes of acute hyperammonemia than in
the 12 months preceding enrollment (5 episodes during the study
versus 9 before enrollment), with peak ammonia dropping from a mean
of 233 .mu.mol/L before enrollment to 166 .mu.mol/L during the
study. Fasting ammonia remained controlled and monthly averages
were at or close to half ULN, ranging from 17 to 22 .mu.mol/L.
Although patients had been instructed to remain fasting before
monthly study visits, some ammonia samples were taken in a
non-fasted state, resulting in average monthly ammonia of slightly
above half ULN.
[0099] In pediatric patients, WASI and CBCL scores were stable in
comparison to baseline. The majority of the BRIEF subscales at
baseline were at or close to 65, consistent with borderline and/or
clinically significant dysfunction. Among 22 pediatric subjects who
completed the neuropsychological testing at 12 months, all BRIEF
domains were improved (lower T scores) with means (SD) at end of
study compared to baseline for Behavioral Regulation Index 53.7
(9.79) vs. 60.4 (14.03) (p<0.05); Metacognition Index 57.5
(9.84) vs. 67.5 (13.72) (p<0.001), and Global Executive Scale
56.5 (9.71) vs. 66.2 (14.02) (p<0.001).
[0100] The significant improvement in executive functions in this
group of pediatric UCD patients indicates the importance of long
term ammonia control and achieving target levels of fasting
ammonia.
Example 6
Correlation of Elevated PAA Levels to Neurological AEs in UCD and
Healthy Subjects
[0101] Elevated plasma levels of PAA may cause symptoms that mimic
those associated with hyperammonemia, including headache, nausea,
somnolence, etc. Since such symptoms are common and nonspecific, an
ammonia level below half the upper limit of normal in a subject
with a nitrogen retention disorder who exhibits such symptoms and
is receiving a PAA prodrug would prompt a physician to check plasma
PAA levels.
[0102] The relationship between elevated PAA levels and
neurological AEs was evaluated in three populations: (1) 130
healthy adults dosed with 4 to 12 mL TID of GPB in a thorough QTc
study, (2) 54 adult and 11 pediatric UCD patients (ages 6-17)
enrolled in one of 3 protocols involving short term (2-4 week)
switchover comparisons of NaPBA vs. GPB, and (3) 77 patients
enrolled in two nearly identical 12-month GPB treatment protocols.
In populations 1 and 2, maximal PAA (i.e., Cmax) levels were
analyzed in relation to neurological AEs as defined by MEDDRA using
an Exact non-parametric Mann-Whitney test and Generalized
Estimating Equations (GEE) with a logit link function and effects
for dose and PAA level. The relationship between PAA levels and the
occurrence of the AEs reported by Thiebault was also explored in
population 3.
[0103] No statistically significant relationship was observed
between neurological AEs and PAA levels for either GPB or NaPBA.
The odds ratio of a neurological AE occurring for each 20 .mu.g/mL
increase in PAA levels for the two drugs combined was 0.95, very
close to 1. Thus, among UCD patients dosed with HPN-100 or NaPBA
over the ranges used in these studies, increasing levels of PAA
(ranging up to 244 .mu.g/mL) were not associated with an increase
in neurological AEs. Similarly, in population 3, PAA levels did not
increase over time and exhibited no apparent relationship to
neurological AEs, which also did not increase in frequency over
time. The pediatric patient with the highest PAA level (410
.mu.g/mL) did not report neurological AEs close to the timing of
the blood draw.
[0104] Unlike UCD subjects, healthy adult volunteers who reported a
nervous system AE had statistically significantly higher PAA
C.sub.max levels than those who did not. While this analysis in
healthy adults is compromised by the fact that PAA levels were not
always available at the time of occurrence of the AEs, as well as
by the small sample size in the higher dose groups, the odds ratio
of 1.75 (p=0.006) suggests that increasing levels of PAA are
associated with increased probability of experiencing a nervous
system AE among healthy adults. AEs reported by healthy adults
generally began within 36 hours of dosing and, among those adults
who remained on study, most resolved with continued dosing.
[0105] A significant relationship between PAA levels and occurrence
of neurological AEs, which generally resolved with continued
dosing, was detected in healthy volunteers. Unlike in healthy
adults, PAA Cmax did not correlate with nervous system AEs in UCD
patients over a similar range of doses and PAA levels. These
findings may reflect metabolic differences among the populations
(e.g., UCD patients exhibit high glutamine levels compared with
healthy humans) and/or metabolic adaptation with continued
dosing.
[0106] Population PK model building was performed on 65 UCD
patients who participated in the short-term switchover Hyperion
studies using NONMEM (version 7.2) based on 2981 ([PBA], [PAA],
[PAGN], and urine PAGN [UPAGN])) data points from 53 adult and 11
pediatric UCD patients (ages 6-17) who participated in 3 switchover
studies of NaPBA and GPB. The median GPB dose, expressed as grams
of PBA per m2, was 8.85 and 7.01 for pediatric and adult subjects,
respectively. Diagnostic plots and statistical comparisons were
used to select among candidate models, and covariates were assessed
by graphical analyses and covariate modeling. Using the final popPK
model and parameter estimates, Monte Carlo simulations were
performed in .about.1000 virtual patients for a range of NaPBA and
GPB doses to predict systemic metabolite exposure and UPAGN
output.
[0107] The final model that best fit the data was characterized by
(a) partial conversion of PBA to PAGN prior to reaching the
systemic circulation, (b) saturable conversion of PAA to PAGN
(Km.about.161 ug/ml), and (c) .about.60% slower PBA absorption when
delivered as GPB vs. NaPBA. Body surface area (BSA) was a
significant covariate such that metabolite clearance was
proportionally related to BSA. Fractional presystemic metabolism of
PBA was higher for adults than for pediatric patients receiving GPB
(43% vs. 14%), whereas the reverse was true for NaPBA (23% vs.
43%). Predicted median PAA exposure based on simulated GPB dosing
at the PBA equivalent of 13 g/m2 of NaPBA was .about.13%-22% lower
in adults than NaPBA (Cmax=82 vs. 106 .mu.g/mL; AUC.sub.0-24=649
vs. 829 .mu.gh/m) and .about.13% higher in pediatric subjects ages
6-17 than NaPBA (Cmax=154 vs. 138 .mu.g/mL; AUC.sub.0-24=1286 vs.
1154 .mu.gh/ml); predicted upper 95th percentile PAA exposure was
below 500 .mu.g/mL and 25%-40% lower for adult subjects on GPB
versus NaPBA and similar for pediatric subjects. Simulated dosing
at the PBA equivalent of .about.5 g/m.sup.2 of NaPBA yielded
similar and less variable PAA exposure for both drugs and for
pediatric and adult patients. Recovery of PBA as UPAGN was very
similar whether delivered orally as GPB or NaPBA.
[0108] These findings based on PopPK modeling and dosing
simulations suggest that while most patients treated with PAA
prodrugs including NaPBA or HPN-100 will have PAA levels below
those reportedly associated with toxicity and while no relationship
between PAA levels and neurological AEs was found on a population
basis, individual patients exhibiting symptoms such as headache or
nausea might be suffering from either hyperammonemia or high PAA
levels and that a fasting ammonia level equal to or below half the
upper limit of normal would prompt the physician to check plasma
PAA levels.
[0109] As stated above, the foregoing is merely intended to
illustrate various embodiments of the present invention. The
specific modifications discussed above are not to be construed as
limitations on the scope of the invention. It will be apparent to
one skilled in the art that various equivalents, changes, and
modifications may be made without departing from the scope of the
invention, and it is understood that such equivalent embodiments
are to be included herein. All references cited herein are
incorporated by reference as if fully set forth herein.
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100:221 (2010) [0116] 7. Liang Biometrika 73:13 (1986) [0117] 8.
Lichter-Konecki Mol Genet Metab 103:323 (2011) [0118] 9. McGuire
Hepatology 51:2077 (2010) [0119] 10. Thibault Cancer Res 54:1690
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