U.S. patent application number 17/165758 was filed with the patent office on 2022-02-24 for treating infections with ceftolozane/tazobactam in subjects having impaired renal function.
This patent application is currently assigned to Merck Sharp & Dohme Corp.. The applicant listed for this patent is Merck Sharp & Dohme Corp.. Invention is credited to Gurudatt A. CHANDORKAR, Elham HERSHBERGER, Gopal KRISHNA, Benjamin MILLER, Alan XIAO.
Application Number | 20220054460 17/165758 |
Document ID | / |
Family ID | 1000005945336 |
Filed Date | 2022-02-24 |
United States Patent
Application |
20220054460 |
Kind Code |
A1 |
KRISHNA; Gopal ; et
al. |
February 24, 2022 |
TREATING INFECTIONS WITH CEFTOLOZANE/TAZOBACTAM IN SUBJECTS HAVING
IMPAIRED RENAL FUNCTION
Abstract
Disclosed are methods of administering cephalosporin/tazobactam
to human patients with end stage renal disease undergoing
hemodialysis and suffering from a complicated intra-abdominal
infection or a complicated urinary tract infection.
Inventors: |
KRISHNA; Gopal; (Stow,
MA) ; CHANDORKAR; Gurudatt A.; (Waltham, MA) ;
HERSHBERGER; Elham; (Lexington, MA) ; MILLER;
Benjamin; (Cambridge, MA) ; XIAO; Alan;
(Lexington, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Merck Sharp & Dohme Corp. |
Rahway |
NJ |
US |
|
|
Assignee: |
Merck Sharp & Dohme
Corp.
Rahway
NJ
|
Family ID: |
1000005945336 |
Appl. No.: |
17/165758 |
Filed: |
February 2, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16525458 |
Jul 29, 2019 |
10933053 |
|
|
17165758 |
|
|
|
|
14481496 |
Sep 9, 2014 |
10376496 |
|
|
16525458 |
|
|
|
|
62046417 |
Sep 5, 2014 |
|
|
|
62002457 |
May 23, 2014 |
|
|
|
61988085 |
May 2, 2014 |
|
|
|
61984299 |
Apr 25, 2014 |
|
|
|
61883579 |
Sep 27, 2013 |
|
|
|
61875358 |
Sep 9, 2013 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/546 20130101;
A61K 31/431 20130101; A61K 9/0019 20130101; A61K 9/19 20130101;
A61K 9/08 20130101; A61K 31/4164 20130101; A61M 1/14 20130101; Y02A
50/30 20180101; A61K 47/183 20130101 |
International
Class: |
A61K 31/431 20060101
A61K031/431; A61K 31/546 20060101 A61K031/546; A61K 9/00 20060101
A61K009/00; A61K 47/18 20060101 A61K047/18; A61K 9/19 20060101
A61K009/19; A61K 9/08 20060101 A61K009/08; A61K 31/4164 20060101
A61K031/4164; A61M 1/14 20060101 A61M001/14 |
Claims
1. A method of treating an infection in a patient having an
estimated creatinine clearance of up to about 50 mL/min, comprising
administering to the patient in need thereof a dose of ceftolozane
and tazobactam in a 2:1 weight ratio between ceftolozane active and
tazobactam active, on two or more successive days of treatment, in
amounts and at a dosing interval effective to provide at least an
unbound concentration of ceftolozane of at least 8 micrograms/mL
for at least 30% of the time between successive treatment days and
unbound tazobactam of about 1 microgram/mL for at least 20% of the
time and about 0.5 microgram/mL for about or higher than 50% of the
time.
2. The method of claim 1, wherein the patient has an estimated CrCL
of 15 to 29 mL/min and a total of 375 mg of the ceftolozane and
tazobactam are administered every 8 hours.
3. The method of claim 1, wherein a total of 250 mg ceftolozane
active and 125 mg tazobactam active is intravenously administered
every 8 hours to the patient having a creatinine clearance of 15-29
ml/min for treating an infection selected from the group consisting
of a complicated intra-abdominal infection (cIAI) and a complicated
urinary tract infection (cUTI).
4. The method of claim 1, wherein the dose is selected from the
table below based on the estimated creatinine clearance (CrCL) of
the patient TABLE-US-00051 Estimated CrCL (mL/min) Recommended
Dosage Regimen for CXA-201 30 to 50 750 mg IV every 8 hours 15 to
29 375 mg IV every 8 hours End stage A single loading dose of 750
mg followed by a 150 mg Renal Disease maintenance dose administered
IV every 8 hours for (ESRD) on the remainder of the treatment
period (on hemodialysis hemodialysis days, the dose should be (HD)
administered at the earliest possible time following completion of
dialysis)
5. The method of claim 4, wherein the infection is selected from
the group consisting of a complicated intra-abdominal infection
(cIAI) and a complicated urinary tract infection (cUTI).
6. The method of claim 5, wherein each dose of ceftolozane and
tazobactam is administered at the same or different durations of
1-4 hours each.
7. The method of claim 5, wherein each dose is administered in a
1-hour intravenous infusion.
8. The method of claim 4, further comprising doubling the dose
administered after the patient receives each hemodialysis.
9. The method of claim 5, wherein the infection is a complicated
intra-abdominal infection, and the method further comprises
administering to the patient a therapeutically effective amount of
metronidazole.
10. The method of claim 9, wherein the complicated intra-abdominal
infection is caused by a microorganism selected from the group
consisting of: Citrobacter freundii, Enterobacter cloacae,
Escherichia coli, Escherichia coli CTX-M-14 extended spectrum
beta-lactamase producing strains, Escherichia coli CTX-M-15
extended spectrum beta-lactamase producing strains, Klebsiella
oxytoca, Klebsiella pneumonia, Klebsiella pneumoniae CTX-M-15
extended spectrum beta-lactamase producing strains, Proteus
mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis,
Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides
vulgatus, Streptococcus anginosus, Streptococcus constellatus, and
Streptococcus salivarius.
11. The method of claim 5, wherein the complicated urinary tract
infection is caused by one of the following Gram-negative
microorganisms: Escherichia coli, Escherichia coli levofloxacin
resistant strains, Escherichia coli CTX-M-14 extended spectrum
beta-lactamase producing strains, Escherichia coli CTX-M-15
extended spectrum beta-lactamase producing strains, Klebsiella
pneumoniae, Klebsiella pneumonia levofloxacin resistant strains,
Klebsiella pneumonia CTX-M-15 extended spectrum beta-lactamase
producing strains, Proteus mirabilis or Pseudomonas aeruginosa.
12. The method of claim 5, wherein the ceftolozane active is
provided as ceftolozane sulfate and the tazobactam active is
provided as tazobactam sodium.
13. The method of claim 5, wherein the pharmaceutical composition
is obtained by reconstituting a mixture comprising a total of 1000
mg ceftolozane active and 500 mg tazobactam active with sterile
water for injection or 0.9% Sodium Chloride for injection, USP to
form a reconstituted solution and withdrawing a portion of the
reconstituted solution and adding it to an infusion bag containing
0.9% Sodium Chloride for Injection, USP or 5% Dextrose Injection,
USP.
14. The method of claim 1, wherein the doses are selected from the
group consisting of: a) a loading dose of 600 mg ceftolozane active
and 300 mg tazobactam active, and a maintenance dose of 300 mg
ceftolozane active and 150 mg tazobactam active; b) a loading dose
of 500 mg ceftolozane active and 250 mg tazobactam active, and a
maintenance dose of 300 mg ceftolozane active and 150 mg tazobactam
active; c) a loading dose of 500 mg ceftolozane active and 250 mg
tazobactam active, and a maintenance dose of 100 mg ceftolozane
active and 50 mg tazobactam active; d) a loading dose of 400 mg
ceftolozane active and 200 mg tazobactam active, and a maintenance
dose of 100 mg ceftolozane active and 50 mg tazobactam active; e)
300 mg Ceftolozane active and 150 mg tazobactam active; f) 100 mg
ceftolozane active and 50 mg tazobactam active.
15. The method of claim 14, where each dose is administered in a
1-hour intravenous infusion.
16. The method of claim 1, wherein the doses are selected from the
group consisting of: a) a loading dose of 600 mg ceftolozane active
and 300 mg tazobactam active, and a maintenance dose of 300 mg
ceftolozane active and 150 mg tazobactam active, all 1-hour
intravenous infusion; b) a loading dose of 500 mg ceftolozane
active and 250 mg tazobactam active, and a maintenance dose of 300
mg ceftolozane active and 150 mg tazobactam active, all 1-hour
intravenous infusion; c) a loading dose of 500 mg ceftolozane
active and 250 mg tazobactam active, and a maintenance dose of 100
mg ceftolozane active and 50 mg tazobactam active, all 1-hour
intravenous infusion; d) a loading dose of 400 mg ceftolozane
active and 200 mg tazobactam active, and a maintenance dose of 100
mg ceftolozane active and 50 mg tazobactam active; e) 300 mg
Ceftolozane active and 150 mg tazobactam active, 1-hour intravenous
infusion; f) 100 mg ceftolozane active and 50 mg tazobactam active,
1-hour intravenous infusion; and g) 300 mg ceftolozane active and
150 mg tazobactam active, 4-hour intravenous infusion.
17. A method of treating an overdose in a patient by reducing the
concentration of ceftolozane in the blood of a subject comprising
subjecting the blood of the patient to hemodialysis for a period of
3-4 hours to reduce the exposure of ceftolozane in the blood of the
subject by 66%.
18. A method of treating an infection in a patient having an
estimated creatinine clearance of about 15-29 mL/min, comprising
intravenously administering to the patient in need thereof a dose
of 375 mg of ceftolozane and tazobactam in a 2:1 weight ratio
between ceftolozane active and tazobactam active, every 8
hours.
19. The method of claim 18, wherein the infection is selected from
the group consisting of a complicated intra-abdominal infection
(cIAI) and a complicated urinary tract infection (cUTI).
20. The method of claim 19, wherein the infection is a complicated
intra-abdominal infection, and the method further comprises
administering to the patient a therapeutically effective amount of
metronidazole.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/481,496, filed Sep. 9, 2014, now U.S. Pat.
No. 10,376,496, which_claims the benefit of U.S. Provisional Patent
Applications 62/046,417 (filed Sep. 5, 2014), 62/002,457 (filed May
23, 2014), 61/875,358 (filed Sep. 9, 2013), 61/883,579 (filed Sep.
27, 2013), and 61/984,299 (filed Apr. 25, 2014), and 61/988,085
(filed May 2, 2014), each of which is incorporated herein by
reference in its entirety.
TECHNICAL FIELD
[0002] This disclosure relates to the administration of
ceftolozane/tazobactam to human patients with impaired renal
function.
BACKGROUND
[0003] The cephalosporin
(6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazo-
l-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carb-
oxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-
-2-ene-2-carboxylate (also referred to as "ceftolozane") is an
antibacterial agent. The antibacterial activity of ceftolozane is
believed to result from its interaction with penicillin binding
proteins (PBPs) to inhibit the biosynthesis of the bacterial cell
wall which acts to stop bacterial replication.
[0004] Ceftolozane can be combined (e.g., mixed) with a
.beta.-lactamase inhibitor ("BLI"), such as tazobactam. Tazobactam
is a BLI against Class A and some Class C .beta.-lactamases, with
well-established in vitro and in vivo efficacy in combination with
active .beta.-lactam antibiotics. The combination of ceftolozane,
or a pharmaceutically acceptable salt thereof and tazobactam or a
pharmaceutically acceptable salt thereof in an amount providing a
2:1 weight ratio between the amount of ceftolozane active and
tazobactam active is an antibiotic pharmaceutical composition
("CXA-201") formulated for parenteral administration. CXA-201
displays potent antibacterial activity in vitro against common
Gram-negative and selected Gram-positive organisms that cause
complicated intra-abdominal infections or complicated urinary tract
infections. Moreover, CXA-201 has demonstrated efficacy in clinical
trials against these infections (See, e.g., Examples 3-5), and the
recommended dosage for patients with normal kidney function
[creatinine clearance (CrCL) >50 mL/min] is 1.5 grams of CXA-201
(1 g ceftolozane active/500 mg tazobactam active) administered
intravenously over one hour every eight hours (See Table 1
below).
TABLE-US-00001 TABLE 1 Dosage of CXA-201 by Infection in Patients
with Creatinine Clearance (CrCL) >50 mL/min Infusion Dose Time
Duration of Infection CXA-201 Frequency (hours) Treatment
Complicated Intra- 1.5 g Every 8 1 4-14 days Abdominal Infections
Hours Complicated Urinary 1.5 g Every 8 1 .sup. 7 days Tract
Infections, Hours including Pyelonephritis
[0005] The intravenous formulation of CXA-201 can be prepared by
reconstituting a fixed dose combination mixture of two active
components (ceftolozane and tazobactam), and intravenously
administering the reconstituted pharmaceutical composition. The
pharmacokinetic (PK) profile of ceftolozane/tazobactam has been
studied in several preclinical and clinical studies. In healthy
volunteers the PK of ceftolozane/tazobactam is dose-proportional
and linear across a wide range of doses (up to 3000 mg/1500 mg as a
single dose) with a terminal elimination half-life (t1/2.beta.) of
approximately 2.5 hours for ceftolozane and 1 hour for tazobactam.
Both ceftolozane and tazobactam are primarily excreted in the
urine; ceftolozane almost completely in the urine as unchanged
parent drug suggesting minimal metabolism, and tazobactam with 80%
as the unchanged parent drug and the remaining as inactive M1
metabolite that is formed via hydrolysis of tazobactam (See, e.g.,
Miller B, Hershberger E, Benziger D, Trinh M, Friedland I.,
"Pharmacokinetics and safety of intravenous ceftolozane-tazobactam
in healthy adult subjects following single and multiple ascending
doses," Antimicrob Agents Chemother. 2012; 56(6):3086-3091).
[0006] Ceftolozane is eliminated through the kidney. Example 7
provides the pharmacokinetics of ceftolozane/tazobactam in healthy
volunteers. In healthy volunteers the PK of ceftolozane/tazobactam
is dose-proportional and linear across a wide range of doses (up to
3000 mg/1500 mg as a single dose) with a terminal elimination
half-life (t.sub.1/2.beta.) of approximately 2.5 hours for
ceftolozane and 1 hour for tazobactam. Both ceftolozane and
tazobactam are primarily excreted in the urine; ceftolozane almost
completely in the urine as unchanged parent drug suggesting minimal
metabolism, and tazobactam with 80% as the unchanged parent drug
and the remaining as inactive M1 metabolite that is formed via
hydrolysis of tazobactam. There is no drug-drug interaction between
ceftolozane and tazobactam when co-administered.
[0007] However, impaired kidney function can result in slower drug
clearance of ceftolozane and in increased plasma drug levels.
Accordingly, the dosing of CXA-201 in Table 1 is not appropriate
for certain patients with advanced renal impairment (including, for
example, patients with creatinine clearance less than about 50
mL/minute, such as patients with moderate to severe renal disease
or patients in end stage renal disease who are undergoing
hemodialysis). Therefore, there remains a medical need for
determining appropriate dosing adjustments for safely and
effectively administering a CXA-201 product to a patient at various
stages of renal function impairment, including treatment of
patients with end stage renal disease (ESRD) (e.g., patients having
a creatinine clearance of less than 15 mL/min).
[0008] Adjustments in methods of administering other parenteral
anti-infective therapies to patients with impaired renal function
do not adequately address the unmet medical need for determining
safe and effective methods of administering ceftolozane/tazobactam
to patients with renal impairment. Modifications in the manner of
administering parenteral anti-infective therapies to treat patients
with impaired renal function include changes in the dose amount
and/or dose interval (including products disclosed, e.g., in FIG.
28). For example, modifications in the parenteral administration of
a pharmaceutical composition to patients with impaired renal
function can include (1) decreasing the individual dose and
increasing the time between doses (e.g., administering 2.25 g of
piperacillin/tazobactam every 8 or 12 hours with an additional 0.75
g following dialysis, instead of 3.375 g administered every 6
hours, for treating indicated infections other than nosocomial
pneumonia), (2) increasing the time between doses (e.g.,
administering 1 g of cefepime hydrochloride on day 1 followed by
500 mg every 24 hours thereafter, instead of 0.5-1 or 2 g
administered every 12 hours, for urinary tract or intra-abdominal
infections), (3) decreasing the amount of individual doses without
changing the time between doses (e.g., administering 200 mg of
ceftaroline fasamil every 12 hours, instead of 600 mg administered
every 12 hours, for certain skin infections or pneumonia), and (4)
not changing the dose amount or time between doses (e.g., when
administering intravenous linezolid or ceftriaxone sodium to a
patient with renal impairment).
[0009] There remains a need for safe and effective methods of
administering a CXA-201 anti-infective product to patients having
various levels of renal impairment as characterized by reduced
creatinine clearance (CrCl).
SUMMARY
[0010] Dosage adjustment of ceftolozane/tazobactam pharmaceutical
compositions is required in patients with moderate (CrCL 30 to 50
mL/min) or severe (CrCL 15 to 29 mL/min) renal impairment and in
patients with end stage renal disease on hemodialysis (ESRD on
HD).
[0011] In one embodiment, methods of administering ceftolozane and
tazobactam in one or more pharmaceutical compositions for treating
a patient in need thereof can comprise administering a dose of
ceftolozane and tazobactam, with or without a loading dose, in
amounts and at a dosing interval effective to provide at least an
unbound concentration of ceftolozane of at least 8 micrograms/mL
for at least 30% of the time between successive treatment days and
unbound tazobactam of about 1 microgram/mL for at least 20% of the
time and about 0.5 microgram/mL for about or higher than 50% of the
time. Preferably, the ceftolozane and tazobactam are administered
in a 2:1 weight ratio between the amount of ceftolozane active and
the amount of tazobactam active.
[0012] In another embodiment, use of a therapeutically effective
amount of a pharmaceutical composition comprising ceftolozane
active and tazobactam active in a 2:1 weight ratio, is disclosed
for treating an infection in a patient., The therapeutically
effective amount can be selected to provide a dose of the
pharmaceutical composition, with or without a loading dose, in
amounts and at a dosing interval therapeutically effective to
provide at least an unbound concentration of ceftolozane of at
least 8 micrograms/mL in the patient for at least 30% of the time
between successive treatment days and unbound tazobactam of about 1
microgram/mL for at least 20% of the time and about 0.5
microgram/mL for about or higher than 50% of the time during the
duration of treatment. Examples of preferred embodiments include:
(1) the use of 750 mg of a pharmaceutical composition comprising
ceftolozane active and tazobactam active in a 2:1 weight ratio for
the treatment of an infection in a patient having a creatinine
clearance rate of about 20-50 mL/min; (2) the use of 375 mg of a
pharmaceutical composition comprising ceftolozane active and
tazobactam active in a 2:1 weight ratio for the treatment of an
infection in a patient having a creatinine clearance rate of about
15-29 mL/min; and (3) the use of a single loading dose of 750 mg
followed by use of a 150 mg maintenance dose of a pharmaceutical
composition comprising ceftolozane active and tazobactam active in
a 2:1 weight ratio administered IV every 8 hours for the remainder
of the treatment period (on hemodialysis days, the dose should be
administered at the earliest possible time following completion of
dialysis).
[0013] In an embodiment, a pharmaceutical composition comprising
ceftolozane active and tazobactam active in a 2:1 weight ratio is
administered to a patient with impaired renal function in
accordance with Table 2A below:
TABLE-US-00002 TABLE 2A Dosage of CXA-201 in Patients with Impaired
Renal Function Estimated CrCL (mL/min) Recommended Dosage Regimen
for CXA-201 30 to 50 750 mg IV every 8 hours 15 to 29 375 mg IV
every 8 hours End stage A single loading dose of 750 mg followed by
a 150 mg Renal Disease maintenance dose administered IV every 8
hours for (ESRD) on the remainder of the treatment period (on
hemodialysis hemodialysis days, the dose should be (HD)
administered at the earliest possible time following completion of
dialysis)
[0014] In a preferred embodiment, the invention provides for the
use of 500 mg ceftolozane active and 250 mg tazobactam active
administered intravenously every 8 hours to a patient having a
creatinine clearance (CrCl) of 30 to 50 ml/min. In a preferred
embodiment, the invention provides for the use of 250 mg
ceftolozane active and 125 mg tazobactam active administered
intravenously every 8 hours to a patient having a creatinine
clearance (CrCl) of 15 to 29 ml/min. In a preferred embodiment, the
invention provides for the use of 500 mg ceftolozane active and 250
mg tazobactam active administered intravenously to a patient with
End Stage Renal Disease (ESRD) undergoing hemodialysis (HD)
followed by use of a maintenance dose of 100 mg ceftolozane active
and 50 mg tazobactam active administered intravenously every 8
hours for the remainder of the treatment period.
[0015] In other embodiments, one or more doses can be administered
at the same or different durations of 1-4 hours each. In other
embodiments, one or more doses are administered 1-4 times per day
at the same or different intervals between doses.
[0016] In other embodiments, the doses are selected from the group
consisting of: [0017] a) a loading dose of 600 mg ceftolozane
active and 300 mg tazobactam active, and a maintenance dose of 300
mg ceftolozane active and 150 mg tazobactam active; [0018] b) a
loading dose of 500 mg ceftolozane active and 250 mg tazobactam
active, and a maintenance dose of 300 mg ceftolozane active and 150
mg tazobactam active; [0019] c) a loading dose of 500 mg
ceftolozane active and 250 mg tazobactam active, and a maintenance
dose of 100 mg ceftolozane active and 50 mg tazobactam active;
[0020] d) a loading dose of 400 mg ceftolozane active and 200 mg
tazobactam active, and a maintenance dose of 100 mg ceftolozane
active and 50 mg tazobactam active; [0021] e) 300 mg ceftolozane
active and 150 mg tazobactam active; and [0022] f) 100 mg
ceftolozane active and 50 mg tazobactam active.
[0023] In certain embodiments, each dose is administered in a
1-hour intravenous infusion.
[0024] In other embodiments, the doses are selected from the group
consisting of: [0025] a) a loading dose of 600 mg ceftolozane
active and 300 mg tazobactam active, and a maintenance dose of 300
mg ceftolozane active and 150 mg tazobactam active, all 1-hour
intravenous infusion; [0026] b) a loading dose of 500 mg
ceftolozane active and 250 mg tazobactam active, and a maintenance
dose of 300 mg ceftolozane active and 150 mg tazobactam active, all
1-hour intravenous infusion; [0027] c) a loading dose of 500 mg
ceftolozane active and 250 mg tazobactam active, and a maintenance
dose of 100 mg ceftolozane active and 50 mg tazobactam active, all
1-hour intravenous infusion; [0028] d) a loading dose of 400 mg
ceftolozane active and 200 mg tazobactam active, and a maintenance
dose of 100 mg ceftolozane active and 50 mg tazobactam active;
[0029] e) 300 mg ceftolozane active and 150 mg tazobactam active,
1-hour intravenous infusion; [0030] f) 100 mg ceftolozane active
and 50 mg tazobactam active, 1-hour intravenous infusion; and
[0031] g) 300 mg ceftolozane active and 150 mg tazobactam active,
4-hour intravenous infusion.
[0032] In another embodiment, the use of a ceftolozane and
tazobactam in one or more pharmaceutical compositions for treating
a patient in need thereof wherein the amount of the
ceftolozane/tazobactam composition dose is doubled.
[0033] In another embodiment, the use of a ceftolozane and
tazobactam in one or more pharmaceutical compositions for treating
a patient in need thereof comprises administering an additional
dose of ceftolozane and tazobactam immediately after the patient
receives each hemodialysis.
[0034] In another embodiment, the use of a ceftolozane and
tazobactam in one or more pharmaceutical compositions for treating
a patient in need thereof comprises doubling the dose administered
after the patient receives each hemodialysis.
[0035] As disclosed herein, methods and uses for safely and
effectively administering ceftolozane in a pharmaceutical
composition (such as a CXA-201 pharmaceutical composition) can
include administering a loading dose of ceftolozane followed by a
maintenance dose of the ceftolzoane in amounts and at a dosing
interval effective to provide a ceftolozane concentration of at
least 8 micrograms/mL in the blood for at least 30% of the time
between successive treatment days.
[0036] In one embodiment, a method for reducing the concentration
of ceftolozane in the blood of a subject is disclosed comprising
subjecting the blood of the patient to hemodialysis for a period of
3-4 hours to reduce the exposure of ceftolozane in the blood of the
subject by 66%.
[0037] In another preferred embodiment, ceftolozane and tazobactam
can be administered in a 2:1 fixed dose combination of ceftolozane
active to tazobactam active ("CXA-201") for treating a patient
having a creatinine clearance of less than 15 mL/minute (e.g., a
patient with end stage renal disease on hemodialysis) by
parenterally administering to the patient a single loading dose of
750 mg of a CXA-201 pharmaceutical composition (i.e., an amount
providing 500 mg of ceftolozane active and 250 mg of tazobactam
active), followed by a 150 mg maintenance dose of the CXA-201
pharmaceutical composition (i.e., an amount providing 100 mg of
ceftolozane active and 50 mg of tazobactam active) administered
every 8 hours for the remainder of the treatment period, where the
duration of therapy is guided by the severity and site of infection
and the patient's clinical and bacteriological progress (Table
2B).
TABLE-US-00003 TABLE 2B Dosage of CXA-201 by Infection in ESRD
Patients Undergoing Hemodialysis Infusion Duration Time of
Infection Dose Frequency (hours) Treatment Complicated A single
loading dose of 750 mg Every 8 1 4-14 days Intra- (500 mg
ceftolozane active/250 mg Hours Abdominal tazobactam active)
followed by a Infections 150 mg (100 mg ceftolozane active/ 50 mg
tazobactam active) maintenance dose administered every 8 hours for
the remainder of the treatment period (on hemodialysis days, the
dose should be administered at the earliest possible time following
completion of dialysis) Complicated A single loading dose of 750 mg
Every 8 1 7 days Urinary Tract (500 mg ceftolozane active/250 mg
Hours Infections, tazobactam active) followed by a including 150 mg
maintenance dose Pyelonephritis administered every 8 hours for the
remainder of the treatment period (on hemodialysis days, the dose
should be administered at the earliest possible time following
completion of dialysis)
[0038] In one embodiment, the loading dose is administered
intravenously over one hour. In another aspect, each maintenance
dose is administered intravenously over one hour. In another
aspect, the maintenance dose is administered every 8 hours. In
another aspect, each maintenance dose is administered intravenously
over one hour every eight hours. In yet another aspect, the loading
dose is administered intravenously over one hour and each
maintenance dose is administered intravenously over one hour every
8 hours.
[0039] Typically, the duration of treatment (including loading dose
and maintenance dose) for complicated intra-abdominal infections is
4-14 days; and the duration of treatment (including loading dose
and maintenance dose) for complicated urinary tract infections is 7
days.
[0040] In an embodiment, the invention provides for the use of
ceftolozane and tazobactam for treating a complicated
intra-abdominal infection or a complicated urinary tract infection
in a human patient having a creatinine clearance of less than 15
mL/minute, comprising intravenously administering to the patient
500 mg of ceftolozane active and 250 mg tazobactam active, followed
by administering one or more additional doses of 100 mg ceftolozane
active and 50 mg of tazobactam active to the patient every 8 hours
for the duration of a treatment period.
[0041] In one embodiment, the 500 mg of ceftolozane active is
co-administered with the 250 mg tazobactam in a single
pharmaceutical composition.
[0042] In one embodiment, the 100 mg of ceftolozane active is
co-administered with the 50 mg tazobactam in a single
pharmaceutical composition.
[0043] In one embodiment, the infection is a complicated
intra-abdominal infection.
[0044] In one embodiment, the use of ceftolozane and tazobactam for
treating a complicated intra-abdominal infection or a complicated
urinary tract infection in a human patient having a creatinine
clearance of less than 15 mL/minute further comprises administering
to the patient a therapeutically effective amount of
metronidazole.
[0045] In another embodiment, the complicated intra-abdominal
infection is caused by a microorganism selected from the group
consisting of: Enterobacter cloacae, Escherichia coli (including
CTX-M-14/15 extended spectrum beta-lactamase (ESBL)-producing
strains), Klebsiella oxytoca, Klebsiella pneumoniae (including
CTX-M-15 ESBL-producing strains), Proteus mirabilis, Pseudomonas
aeruginosa, Bacteroides fragilis, Bacteroides ovatus, Bacteroides
thetaiotaomicron, Bacteroides vulgatus, Streptococcus anginosus,
Streptococcus constellatus, and Streptococcus salivarius.
[0046] In one embodiment, the complicated urinary tract infection
is caused by one of the following Gram-negative microorganisms:
Escherichia coli (including levofloxacin resistant and/or
CTX-M-14/15 ESBL-producing strains), Klebsiella pneumoniae
(including levofloxacin resistant and/or CTX-M-15-ESBL producing
strains), Proteus mirabilis, and Pseudomonas aeruginosa.
[0047] In one embodiment, the ceftolozane active is provided as
ceftolozane sulfate and the tazobactam active is provided as
tazobactam sodium.
[0048] In one embodiment, the pharmaceutical composition is
obtained by reconstituting a mixture comprising a total of 1000 mg
ceftolozane active and 500 mg tazobactam active with sterile water
for injection or 0.9% Sodium Chloride for injection, USP to form a
reconstituted solution and withdrawing a portion of the
reconstituted solution and adding it to an infusion bag containing
0.9% Sodium Chloride for Injection, USP or 5% Dextrose Injection,
USP.
[0049] In one embodiment, the ceftolozane active is provided as
ceftolozane sulfate and the tazobactam is provided as tazobactam
sodium.
[0050] In one embodiment, the pharmaceutical composition is
administered intravenously over one hour.
[0051] In one embodiment, provided herein is the use of ceftolozane
and tazobactam for treating a complicated intra-abdominal infection
or a complicated urinary tract infection, wherein [0052] a. the 500
mg of ceftolozane active is co-administered with the 250 mg
tazobactam in a first single pharmaceutical composition; [0053] b.
the 100 mg of ceftolozane active is co-administered with the 50 mg
tazobactam in a second single pharmaceutical composition; [0054] c.
the ceftolozane active is provided as ceftolozane sulfate and the
tazobactam active is provided as tazobactam sodium; [0055] d. the
first pharmaceutical composition is obtained by reconstituting a
mixture comprising ceftolozane sulfate and tazobactam sodium with
sterile water for injection or 0.9% Sodium Chloride for injection,
USP to form a reconstituted solution and withdrawing at least a
portion of the reconstituted solution and adding it to an infusion
bag containing 0.9% Sodium Chloride for Injection, USP or 5%
Dextrose Injection, USP; [0056] e. the first pharmaceutical
composition and the second pharmaceutical compositions are each
separately administered intravenously over one hour; [0057] f. the
complicated intra-abdominal infection is caused by a microorganism
selected from the group consisting of: Enterobacter cloacae,
Escherichia coli (including CTX-M-14/15 extended spectrum
beta-lactamase (ESBL)-producing strains), Klebsiella oxytoca,
Klebsiella pneumoniae (including CTX-M-15 ESBL-producing strains),
Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis,
Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides
vulgatus, Streptococcus anginosus, Streptococcus constellatus, and
Streptococcus salivarius; or [0058] g. the complicated urinary
tract infection is caused by one of the following Gram-negative
microorganisms: Escherichia coli (including levofloxacin resistant
and/or CTX-M-14/15 ESBL-producing strains), Klebsiella pneumoniae
(including levofloxacin resistant and/or CTX-M-15-ESBL producing
strains), Proteus mirabilis, and Pseudomonas aeruginosa.
[0059] In another embodiment, the invention provides for the use of
ceftolozane and tazobactam for treating a complicated
intra-abdominal infection or a complicated urinary tract infection
in a human patient with end stage renal disease with a
ceftolozane/tazobactam composition that includes ceftolozane or a
pharmaceutically acceptable salt thereof combined in a fixed dose
ratio with tazobactam or a pharmaceutically acceptable salt thereof
in an amount providing a 2:1 weight ratio between the amount of
ceftolozane active and the amount of tazobactam active in the
ceftolozane/tazobactam composition, where the method comprises
intravenously administering to the human patient a single loading
dose comprising 750 mg of the ceftolozane/tazobactam composition
followed by a maintenance dose of the antibiotic composition
comprising 150 mg of the ceftolozane/tazobactam composition.
[0060] In one embodiment, the infection is a complicated urinary
tract infection and the method further comprises repeatedly
administering the 150 mg maintenance dose of the
ceftolozane/tazobactam composition every 8 hours for up to a total
of 7 days.
[0061] In one embodiment, the infection is a complicated
intra-abdominal infection and the method further comprises
repeatedly administering the 150 mg maintenance dose of the
ceftolozane/tazobactam composition every 8 hours for a total of
4-14 days.
[0062] In one embodiment, the use of ceftolozane and tazobactam for
treating a complicated intra-abdominal infection or a complicated
urinary tract infection further comprises administering to the
patient a therapeutically effective amount of metronidazole to the
human patient separately from the ceftolozane and tazobactam.
[0063] In one embodiment, the ceftolozane active is provided as
ceftolozane sulfate and the tazobactam is provided as tazobactam
sodium.
[0064] In another embodiment, the invention provides for the use of
ceftolozane and tazobactam for treating a complicated
intra-abdominal infection or a complicated urinary tract infection
in a human patient, wherein [0065] a. the ceftolozane active is
provided as ceftolozane sulfate and the tazobactam active is
provided as tazobactam sodium; [0066] b. the loading dose is
obtained by reconstituting a mixture comprising ceftolozane sulfate
and tazobactam sodium with sterile water for injection or 0.9%
Sodium Chloride for injection, USP to form a reconstituted solution
and withdrawing at least a portion of the reconstituted solution
and adding it to an infusion bag containing 100 mL of 0.9% Sodium
Chloride for Injection, USP or 5% Dextrose Injection, USP; [0067]
c. the loading dose and each maintenance dose are each separately
administered intravenously over one hour; [0068] d. the complicated
intra-abdominal infection is caused by a microorganism selected
from the group consisting of: Citrobacter freundii, Enterobacter
cloacae, Escherichia coli, Escherichia coli CTX-M-14 extended
spectrum beta-lactamase producing strains, Escherichia coli
CTX-M-15 extended spectrum beta-lactamase producing strains,
Klebsiella oxytoca, Klebsiella pneumonia, Klebsiella pneumoniae
CTX-M-15 extended spectrum beta-lactamase producing strains,
Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis,
Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides
vulgatus, Streptococcus anginosus, Streptococcus constellatus, and
Streptococcus salivarius; or [0069] e. the complicated urinary
tract infection is caused by one of the following Gram-negative
microorganisms: Escherichia coli, Escherichia coli levofloxacin
resistant strains, Escherichia coli CTX-M-14 extended spectrum
beta-lactamase producing strains, Escherichia coli CTX-M-15
extended spectrum beta-lactamase producing strains, Klebsiella
pneumoniae, Klebsiella pneumonia levofloxacin resistant strains,
Klebsiella pneumonia CTX-M-15 extended spectrum beta-lactamase
producing strains, Proteus mirabilis or Pseudomonas aeruginosa.
[0070] On hemodialysis days, the dose can be administered at the
earliest possible time following completion of hemodialysis. For
example, the loading dose can be followed immediately after
completion of hemodialysis (e.g., within 3 hours, 2 hours, 1 hour,
0.5 hours, 0.25 hours following completion of hemodialysis) by a
maintenance dose comprising 100 mg of ceftolozane active and 50 mg
tazobactam active. CXA-201 can be administered as a fixed dose
ratio of ceftolozane and tazobactam to these patients according to
the methods of treatment disclosed herein. These methods of
treating ESRD patients undergoing hemodialysis can be used to treat
patients having a complicated intra-abdominal infection and/or a
complicated urinary tract infection as disclosed herein.
[0071] The invention is based in part on the discovery that,
following administration of a single 1.5 g intravenous dose of
CXA-201 to healthy male adults, greater than 95% of ceftolozane was
excreted in the urine as unchanged parent drug. More than 80% of
tazobactam was excreted as the parent compound with the remainder
excreted as the tazobactam M1 metabolite. After a single dose of
CXA-201, renal clearance of ceftolozane (3.41-6.69 L/h) was similar
to plasma CL (4.10 to 6.73 L/h) and similar to the glomerular
filtration rate for the unbound fraction, suggesting that
ceftolozane is eliminated by the kidney via glomerular filtration.
Furthermore, the probability of target attainment (PTA) exceeded
90% for a minimum inhibitory concentration (MIC) up to 8 .mu.g/mL
for ceftolozane across all the tested scenarios in Example 9. Out
of all the tested scenarios, the 500 mg/250 mg C/T single loading
dose followed by 100 mg/50 mg every 8 hours maintenance dose via
1-hr infusion achieved a >99% PTA against all targets up to an
MIC of 8 .mu.g/mL on day 1 and >97% PTA on all other days
without HD. The PTA for bactericidal activity on post HD days was
89%.
BRIEF DESCRIPTION OF THE DRAWINGS
[0072] FIG. 1A shows the demographic and baseline patient
characteristics of the mMITT population. No antibiotics were
permitted within 48 hours prior to obtaining the baseline urine
culture. Urinary catheter was removed before end of treatment in
all but three patients in the ceftolozane/tazobactam group and one
patient in the levofloxacin group. cLUTI denotes complicated lower
urinary tract infections, mMITT microbiological modified
intent-to-treat.
[0073] FIG. 1B shows the susceptibility of baseline uropathogens to
ceftolozane/tazobactam and levofloxacin (mMITT, microbiologically
modified intent-to-treat). Notes: Percentages are calculated as
100.times.(n/N). If fewer than 10 patients reported an isolate
overall, the isolate was reported alongside other isolates of the
same genus which meet the same criteria. Not all isolates were
received at the central microbiology laboratory for susceptibility
testing. For ceftolozane/tazobactam,
Susceptible/Indeterminate/Resistant breakpoints were defined as MIC
.ltoreq.8 mg/1; MIC=16 mg/1; and MIC .gtoreq.32 mg/1,
respectively.
[0074] FIG. 1C shows the primary and secondary analysis end points
at the Test-of-Cure visit (mMITT and per-protocol populations).
[0075] FIG. 1D shows the composite cure at the Test-of-Cure visit,
according to subgroups (mMITT population). ESBL (extended-spectrum
.beta.-lactamase) positive includes isolates of E. coli, K
pneumoniae, P. mirabilis, E. cloacae, Enterobacter aerogenes, and
Serratia marcescens. cLUTI denotes complicated lower urinary tract
infection, mMITT microbiological modified intent-to-treat.
[0076] FIG. 1E shows a summary of Adverse Events Occurring in 1% of
Patients in Either Treatment Group (Safety Population).
[0077] FIG. 1F shows a summary of serious adverse events by system
organ class (safety population).
[0078] FIG. 2 shows summary of published clinical studies of
ceftolozane and/or ceftolozane/tazobactam. The following
abbreviations apply: cIAI, complicated intra-abdominal infections;
cUTI, complicated urinary tract infections; ESRD, end-stage renal
disease; IV, intravenous; q8h, every 8 hours; and RI, renal
impairment.
[0079] FIG. 3 shows the baseline characteristics of subjects
included in the population PK model. The following abbreviations
apply: BMI, body mass index; CrCL, creatinine clearance; RI, renal
impairment; .sup.aincludes patients with cUTIs or cIAIs,
.sup.bincludes patients with cIAIs; .sup.cCrCL ranges for normal,
mild, moderate and severe renal impairment were .gtoreq.90 mL/min,
.gtoreq.50-<90 mL/min, .gtoreq.30-<50 mL/min and
.gtoreq.15-<30 mL/min, respectively. CrCL estimated by the
Cockcroft-Gault formula.
[0080] FIG. 4 shows a Tornado plot showing the effect of infection,
renal impairment (based on CrCl categories over a standardized
range) and BSV on the relative CL of [A] ceftolozane and [B]
tazobactam. Numbers represent the CL range. The following
abbreviations apply: BSV, between subject variability; CL,
clearance; CrCL, creatinine clearance.
[0081] FIG. 5 shows final population-pharmacokinetic models derived
for [A] ceftolozane and [B] tazobactam. The following abbreviations
apply: BSV, between-subject variability; CL, clearance; CL2,
peripheral clearance; CrCl, creatinine clearance; IAI,
intra-abdominal infection; NA, not applicable; RSE, relative
standard error; UTI, urinary tract infection; Vc, central volume of
distribution; Vp, peripheral volume of distribution.
[0082] FIG. 6 shows population and individual predicted versus
observed plasma concentrations of [A] ceftolozane and [B]
tazobactam for the final PK model (Goodness of fit plot). The
following abbreviations apply: DENT: Identity line; LOESS: Locally
weighted scatter smoothing.
[0083] FIGS. 7A and 7B show two graphs of the simulated probability
of target attainment on day 1 (top, with loading dose) and day 3
(bottom, post HD) in patients with ESRD on HD (n=5000) after
administration of a loading dose of 500 mg/250 mg C/T, followed in
8 hr by 100 mg/50 mg C/T, 1-hr IV infusion every 8 hours.
[0084] FIG. 8 shows the baseline characteristics of subjects.
.sup.a RI, renal impairment. .sup.b CrCl estimated by the
Cockcroft-Gault formula. .sup.c BMI, body mass index. .sup.d NA,
not applicable.
[0085] FIG. 9 shows the median pharmacokinetic values for
ceftolozane following single-dose administration of intravenous
ceftolozane/tazobactam. .sup.a C/T, ceftolozane/tazobactam. .sup.b
The t.sub.1/2 on HD was calculated from the terminal elimination
phase post HD. .sup.c Incomplete urine recovery over 48 h. .sup.d
ND, not determined. As a majority of the subjects with ESRD were
anuric, CL.sub.r could not be determined.
[0086] FIG. 10 shows the median pharmacokinetic values for
tazobactam following single-dose administration of intravenous
ceftolozane/tazobactam. .sup.a The t.sub.1/2 on HD was calculated
from the terminal elimination phase post HD.
[0087] FIG. 11 shows the median (range) plasma concentration-time
profiles of [A] ceftolozane and [B] tazobactam following
single-dose administration of intravenous ceftolozane/tazobactam
(semi-log plot). .sup.aC/T, ceftolozane/tazobactam. .sup.bRI, renal
impairment.
[0088] FIG. 12 shows regression plots of [A] ceftolozane and [B]
tazobactam plasma clearance versus CrCl following single-dose
administration of intravenous ceftolozane/tazobactam. .sup.aC/T,
ceftolozane/tazobactam. .sup.bRI, renal impairment.
[0089] FIG. 13 shows the median (range) plasma concentration-time
profiles of ceftolozane and tazobactam following administration of
intravenous ceftolozane/tazobactam (500 mg/250 mg) in subjects with
ESRD on [A] day 1 (post-HD) and [B] day 4 (on HD) (semi-log
plot).
[0090] FIG. 14A shows an overview of the clinical study included in
this analysis.
[0091] FIG. 14B shows the individual plasma concentrations of
ceftolozane included for population PK analysis.
[0092] FIG. 14C shows the individual plasma concentrations of
tazobactam included for population PK analysis.
[0093] FIG. 14D shows the characteristics of the dialysis criteria
in the safety population. Unless otherwise indicated herein,
clinical data disclosed herein obtained in patients on hemodialysis
(HD) with end stage renal disease (ESRD) subjects, including BUN
collected before and after dialysis, was obtained using HD dialysis
parameters provided in FIG. 14. Note: A=Asian; B=Black or African
American; P=Native Hawaiian or Other Pacific islander; I=American
Indian or Alaska Native; O=Other; W=White; H=Hispanic or Latino;
N=Not Hispanic or Latino; M=Male; F=Female. Unless otherwise
indicated herein, subjects underwent HD for 3 to 4 hours using a
high-flux membrane (either 1.4, 1.8, or 1.9 m2) on Days 1, 4, and 6
as scheduled. Average blood flow rate was 264 to 600 mL/min and
average dialysis flow rate was either 600 or 800 mL/min for all
subjects with ESRD.
[0094] FIG. 15 shows the two-compartment PK structure model for
ceftolozane and tazobactam.
[0095] FIG. 16 shows the observed individual plasma
concentration-time profiles of ceftolozane in six subjects with
ESRD/hemodialysis.
[0096] FIG. 17 shows the observed individual plasma
concentration-time profiles of tazobactam in six subjects with
ESRD/Hemodialysis.
[0097] FIG. 18 shows the goodness-of-fit of the population PK model
for ceftolozane. Note: DV stands for measured concentrations; PRED
stands for model-predicted population concentrations; IPRED stands
for model-predicted individual concentrations; CWRES stands for
conditional weighted residuals.
[0098] FIG. 19 shows the Visual Predictive Check (VPC) of the
population PK model for ceftolozane. Note: gray, yellow and gray
bands represent the model-predicted 5th-95th confidence interval of
the model-predicted (green) and observed (red) 5.sup.th (dashed
line), 50th (solid line) and 95th (dashed line) percentile,
respectively.
[0099] FIG. 20 shows the individual fitting of the ceftolozane PK
model. Note: symbols stand for measured concentrations; lines stand
for model-predicted concentrations; IVAR stand for time since first
dose; IPRED and DV stand for model-predicted and measured
individual concentrations, respectively; i, Cobs stand for the
i.sup.th individual patient number.
[0100] FIG. 21 shows the goodness-of-fit of the population PK model
for tazobactam. In FIG. 21, DV stands for measured concentrations;
PRED stands for model-predicted population concentrations; IPRED
stands for model-predicted individual concentrations; CWRES stands
for conditional weighted residuals.
[0101] FIG. 22 shows the Visual Predictive Check (VPC) of the
population PK model for tazobactam. In FIG. 22, the gray, yellow
and gray bands represent the model-predicted 5th-95th confidence
interval of the model-predicted (green) and observed (red) 5.sup.th
(dashed line), 50th (solid line) and 95th (dashed line) percentile,
respectively.
[0102] FIG. 23 shows the individual fitting of the ceftolozane PK
model. In FIG. 23, symbols stand for measured concentrations; lines
stand for model-predicted concentrations; IVAR stand for time since
first dose; IPRED and DV stand for model-predicted and measured
individual concentrations, respectively; i, Cobs stand for the
i.sup.th individual patient number.
[0103] FIG. 24 shows the simulated total ceftolozane plasma
concentration-time profiles in subjects with ESRD for the dosing
regimen: a Loading Dose of 500 mg ceftolozane/250 mg
tazobactam+maintenance doses of 100 mg ceftolozane/50 mg
tazobactam, all for 1-hr infusion every 8 hours. (BSV=50% in log
scale and N=5000). In FIG. 24, the solid line represents median
concentrations and the dashed line represents the lower 10th
percentile of the simulated concentrations; the gray area
represents the 5th-95th percentiles. All BSVs were set at log-scale
50% (variance of 0.25) except for hemodialysis.
[0104] FIG. 25 shows the simulated total tazobactam plasma
concentration-time profiles in subjects with ESRD for the dosing
regimen: a loading dose of 500 mg ceftolozane/250 mg
tazobactam+maintenance doses of 100 mg ceftolozane/50 mg
tazobactam, all for 1-hr infusion every 8 hours. (BSV=50% in log
scale and N=5000). In FIG. 25, the solid line represents median
concentrations and the dashed line represents the lower 10th
percentile of the simulated concentrations; the gray area
represents the 5th-95th percentiles. All BSVs were set at 50%
(variance of 0.25) except for hemodialysis.
[0105] FIG. 26 shows the simulated daily free-ceftolozane %
T>MIC targets by MIC values in patients with ESRD for the dosing
regimen: a loading dose of 500 mg ceftolozane/250 mg
tazobactam+maintenance doses of 100 mg ceftolozane/50 mg
tazobactam, all for 1-hr infusion every 8 hours. (BSV=50% in log
scale and n=5000). Note: fT>MIC stands for free-drug percentage
of time above MIC.
[0106] FIG. 27 shows the simulated daily free-tazobactam % T>MEC
targets by MEC values in patients with ESRD for the dosing regimen:
a loading dose of 500 mg ceftolozane/250 mg tazobactam+maintenance
doses of 100 mg ceftolozane/50 mg tazobactam, all for 1-hr infusion
every 8 hours. (BSV=50% in log scale and N=5000). Note: ft>MEC
represents free-drug % time above a minimum efficacious
concentration.
[0107] FIG. 28 shows a dosing table for commonly prescribed
antibiotics.
[0108] FIG. 29 shows the observed individual plasma
concentration-time profiles of ceftolozane (A) and tazobactam (B)
in 6 patients with ESRD/hemodialysis.
[0109] FIGS. 30A and 30B show that the 500 mg/250 mg C/T single
loading dose followed by 100 mg/50 mg every 8 hours maintenance
dose via 1-hr infusion achieved a >99% PTA against all targets
up to an MIC of 8 .mu.g/mL on day 1 (FIG. 30A) and >97% PTA on
all other days without HD. The PTA for bactericidal activity on
post HD days was 89% (FIG. 30B).
[0110] FIGS. 30C and 30D show the simulated daily free-tazobactam %
T>MEC targets by MIC values in patients with ESRD on day 1, no
hemodialysis (FIG. 30C) and day 3, post hemodialysis (FIG. 30D).
Dosing regimen: a loading dose of 500 mg/250 mg
ceftolozane/tazobactam+maintenance doses of 100 mg/50 mg, all for
1-h infusion every 8 hours (BSV=50% in log scale and N=5000).
[0111] FIG. 31 shows the mean (SD) ceftolozane plasma
concentrations over time after therapeutic (1.5 g) and
supratherapeutic (4.5 g) intravenous 1-hour infusions of
Ceftolozane/Tazobactam (Tables 28-29).
CXA-101/TAZ=ceftolozane/tazobactam; SD=standard deviation.
[0112] FIG. 32 shows the mean (SD) tazobactam plasma concentrations
over time after therapeutic (1.5 g) and supratherapeutic (4.5 g)
intravenous 1-hour infusions of ceftolozane/tazobactam (Tables
28-29). CXA-101/TAZ=ceftolozane/tazobactam; SD=standard
deviation.
[0113] FIG. 33 shows the individual and mean (SD) PK parameters
(CL/WT) of ceftolozane (Top Panel) and tazobactam (Bottom Panel) by
gender after a therapeutic (1.5 g) intravenous 1-hour infusion of
ceftolozane/tazobactam (Tables 28-29). CL/WT=total body clearance
from plasma adjusted for weight; SD=standard deviation.
[0114] FIGS. 34A-E show the percentage of simulated patients
achieving free-drug % T>MIC targets for Enterobacteriaceae by
MIC at steady-state following administration of [A] 1000/500 mg
Ceftolozane/Tazobactam over 1 hour q8h (High Normal Renal
Function), [B] 1000/500 mg Ceftolozane/Tazobactam over 1 hour q8h
(Normal Renal Function), [C] 1000/500 mg Ceftolozane/Tazobactam
over 1 hour q8h (Mild Renal Impairment), [D] 500/250 mg
Ceftolozane/Tazobactam over 1 hour q8h (Moderate Renal Impairment)
and [E] 250/125 mg Ceftolozane/Tazobactam over 1 hour q8h (Severe
Renal Impairment) dosing regimens overlaid on histograms showing
the clinical trial program MIC distributions for TOL/TAZ against
Enterobacteriaceae. FIGS. 35A-E show the percentage of simulated
patients achieving free-drug % T>MIC targets for
Enterobacteriaceae by MIC at steady-state following administration
of [A] 2000/1000 mg 2000/1000 mg Ceftolozane/Tazobactam over 1 hour
q8h (High Normal Renal Function), [B] 2000/1000 mg
Ceftolozane/Tazobactam over 1 hour q8h (Normal Renal Function), [C]
2000/1000 mg Ceftolozane/Tazobactam over 1 hour q8h (Mild Renal
Impairment), [D] 1000/500 mg Ceftolozane/Tazobactam over 1 hour q8h
(Moderate Renal Impairment), [E] 500/250 mg Ceftolozane/Tazobactam
over 1 hour q8h (Severe Renal Impairment) dosing regimens overlaid
on histograms showing the clinical trial program MIC distributions
for TOL/TAZ against Enterobacteriaceae.
[0115] FIG. 36 is a graph showing the plasma concentration (Median
and Range) versus time profile for ceftolozane during
non-hemodialysis in subjects with ESRD (Study Day 1).
[0116] FIG. 37 is a graph showing the plasma Concentration (Median
and Range) versus time profile for tazobactam during
non-hemodialysis in subjects with ESRD (Study Day 1).
[0117] FIG. 38 is graph showing the plasma Concentration (Median
and Range) versus time profile for the M-1 metabolite of tazobactam
during non-hemodialysis in Subjects with ESRD (Study Day 1).
[0118] FIG. 39 is a graph showing the plasma concentration (Median
and Range) versus time profile for ceftolozane in subjects with
ESRD during HD (Study Day 4).
[0119] FIG. 40 is a graph of the plasma Concentration (Median and
Range) versus time profile for tazobactam in subjects with ESRD
during HD (Study Day 4).
[0120] FIG. 41 is a graph showing the plasma Concentration (Median
and Range) versus time profile for the M-1 metabolite of tazobactam
in subjects with ESRD during HD (Study Day 4).
[0121] FIG. 42 is a graph showing the plasma Concentration (Median
and Range) versus time profile for ceftolozane in subjects with
ESRD (Start of Dosing to End of Dialysis).
[0122] FIG. 43 is a graph showing plasma Concentration (Median and
Range) versus time profile for tazobactam in subjects with ESRD
(Start of Dosing to End of Dialysis)
[0123] FIG. 44 is a graph showing the plasma Concentration (Median
and Range) versus time profile for the M-1 Metabolite of tazobactam
in subjects with ESRD (Start of Dosing to End of Dialysis).
DETAILED DESCRIPTION
[0124] Ceftolozane (formula (I) below) is a cephalosporin
antibacterial agent, also referred to as CXA-101, FR264205, or by
chemical names such as
(6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyr-
azol-2-ium-2-yl)methyl]-7-({2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-ca-
rboxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]o-
ct-2-ene-2-carboxylate, and
7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methyl
ethoxyimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-p-
yrazolio}methyl-3-cephem-4-carboxylate. The antibacterial activity
of ceftolozane is believed to result from its interaction with
penicillin binding proteins (PBPs) to inhibit the biosynthesis of
the bacterial cell wall which acts to stop bacterial
replication.
##STR00001##
[0125] Unless otherwise indicated herein, the term "ceftolozane"
refers to pharmaceutically acceptable salts of ceftolozane as well
as ceftolozane free base. Ceftolozane sulfate is an example of a
pharmaceutically acceptable ceftolozane salt of the compound of
formula (I) that can be formulated for intravenous administration
or infusion. As used herein, unless otherwise indicated, the term
"ceftolozane active" refers to the active portion of a salt form of
ceftolozane (e.g., ceftolozane sulfate), i.e., the free base form
of ceftolozane. As used herein, unless otherwise indicated, the
phrase "1,000 mg of ceftolozane as ceftolozane active" refers to an
amount of ceftolozane in any form, including a ceftolozane salt
(e.g., ceftolozane sulfate), in an amount that provides 1,000 mg of
the ceftolozane active moiety. As used herein, "TOL" can refer to
ceftolozane or a pharmaceutically acceptable salt thereof.
[0126] Ceftolozane can be combined with the .beta.-lactamase
inhibitor ("BLI") tazobactam to form an antibiotic pharmaceutical
composition suitable for intravenous administration. Tazobactam is
a BLI against Class A and some Class C .beta.-lactamases, with in
vitro and in vivo efficacy in combination with active beta-lactam
antibiotics. The term "tazobactam" refers to the free acid
tazobactam form of formula (II), as well as pharmaceutically
acceptable salts of the compound of formula (II)).
##STR00002##
[0127] Commonly used tazobactam salts include the sodium salt or
arginine salt. Tazobactam can also be a hydrate or solvate.
"Tazobactam active" refers to the active portion of a salt form of
tazobactam, i.e., tazobactam free acid. For example, "500 mg of
tazobactam as tazobactam active" refers to an amount of the salt
form of tazobactam (e.g., tazobactam sodium or tazobactam arginine)
effective to provide 500 mg of tazobactam active. As used herein,
"TAZ" can refer to tazobactam or a pharmaceutically acceptable salt
thereof.
[0128] A CXA-201 composition includes ceftolozane (e.g., as a
pharmaceutically acceptable ceftolozane salt) and tazobactam (e.g.,
as a pharmaceutically acceptable tazobactam salt) in amounts that
provide a 2:1 ratio between the amount of ceftolozane active and
the amount of the tazobactam active. A preferred antibiotic
composition used in the disclosed methods contains 2:1 w/w of
ceftolozane active/tazobactam active formulated for parenteral
administration. In one aspect, the antibiotic composition is
referred to as "CXA-201" and comprises ceftolozane sulfate and
tazobactam sodium in sufficient quantities to provide 2:1 w/w of
ceftolozane active/tazobactam active. In another aspect, CXA-201 is
formulated for parenteral administration. As used herein, "TOL/TAZ"
refers to a CXA-201 composition.
[0129] CXA-201 can be provided as a lyophilized powder of
ceftolozane sulfate and tazobactam sodium ready for reconstitution.
In one aspect, the unit dosage form of CXA-201 is provided in a
vial ready for reconstitution. The pharmaceutical composition can
be obtained by combining the ceftolozane composition with a
(second) tazobactam composition (e.g., preferably, but not
necessarily, prepared in the absence of ceftolozane) by forming a
second solution comprising tazobactam. The tazobactam can be
included in an amount providing about 5 mg of tazobactam active per
10 mg ceftolozane active (i.e., a 1:2 weight ratio of tazobactam
active to ceftolozane active). Tazobactam is a beta-lactamase
inhibitor in its free acid form. Unless otherwise indicated,
tazobactam can be a free acid, a sodium salt, an arginine salt, or
a hydrate or solvate thereof. In one embodiment, the tazobactam in
the (second) tazobactam composition is tazobactam acid and the
second composition further comprises sodium bicarbonate or sodium
hydroxide. Lyophilizing tazobactam in the presence of sodium
bicarbonate or sodium hydroxide forms a lyophilized tazobactam
sodium, which can then be further blended with the (first)
lyophilized ceftolozane composition.
[0130] Pharmaceutical compositions can be obtained by
lyophilization. Specific methods of lyophilization are described in
Remington's Pharmaceutical Sciences, Chapter 84, page 1565,
Eighteenth Edition, A. R. Gennaro, (Mack Publishing Co., Easton,
Pa., 1990).
[0131] Pharmaceutical compositions comprising ceftolozane and
tazobactam can be formulated to treat infections by parenteral
administration (including subcutaneous, intramuscular, and
intravenous) administration. Pharmaceutical compositions may
additionally comprise excipients, stabilizers, pH adjusting
additives (e.g., buffers) and the like. Non-limiting examples of
these additives include sodium chloride, citric acid and
L-arginine. For example, the use of sodium chloride results in
greater stability; L-arginine is used to adjust pH and to increase
the solubility of ceftolozane; and citric acid is used to prevent
discoloration of the product, due to its ability to chelate metal
ions. In one particular embodiment, the pharmaceutical compositions
described herein are formulated for administration by intravenous
injection or infusion.
[0132] The pharmaceutical antibiotic compositions can be provided
in a unit dosage form container (e.g., in a vial or bag, or the
like). The unit dosage form can be dissolved with a
pharmaceutically acceptable carrier, and then intravenously
administered. The unit dosage form comprises ceftolozane active and
tazobactam active, typically 1000 mg ceftolozane active as
ceftolozane sulfate and 500 mg of tazobactam active as tazobactam
sodium. The unit dosage forms are commonly stored in vials.
[0133] In one aspect, provided herein is a unit dosage form
container (e.g., a bag, vial or the like) containing a unit dosage
form of a pharmaceutical composition formulated for parenteral
administration for the treatment of complicated intra-abdominal
infections, the pharmaceutical composition comprising a
therapeutically effective amount of ceftolozane sulfate and
tazobactam in a ratio of 1,000 mg ceftolozane active per 500 mg of
tazobactam active, the pharmaceutical composition obtained by a
process comprising the steps of:
[0134] a. lyophilizing a first aqueous solution in the absence of
tazobactam, the first aqueous solution comprising ceftolozane
sulfate, about 487 mg of sodium chloride per 1,000 mg of
ceftolozane active, L-arginine and/or citric acid in an amount
effective to adjust the pH of the first aqueous solution to 5-7
(e.g., 6-7) prior to lyophilization to obtain a first lyophilized
ceftolozane composition,
[0135] b. lyophilizing a second solution in the absence of
ceftolozane, the second solution comprising tazobactam being
lyophilized to form a second lyophilized tazobactam composition;
and
[0136] c. blending the first lyophilized ceftolozane composition
and the second lyophilized tazobactam composition to obtain a
blended pharmaceutical composition in the unit dosage form.
[0137] In one embodiment of the unit dosage form container, the
tazobactam in the second solution is tazobactam acid, and wherein
the tazobactam acid in the second solution is lyophilized in the
presence of sodium bicarbonate or sodium hydroxide, thereby forming
lyophilized tazobactam sodium in the second lyophilized tazobactam
solution.
[0138] The pharmaceutical compositions provided herein comprising
ceftolozane sulfate and tazobactam in a ratio of 1,000 mg
ceftolozane active per 500 mg of tazobactam active, can be obtained
by a process comprising the steps of:
[0139] a. lyophilizing a first aqueous solution in the absence of
tazobactam, the first aqueous solution comprising ceftolozane
sulfate at a pH of 5-7 (e.g., 6-7) prior to lyophilization to
obtain a first lyophilized ceftolozane composition,
[0140] b. blending the first lyophilized ceftolozane composition
with tazobactam to obtain an antibacterial composition.
[0141] As provided herein, ceftolozane can be stabilized in a
pharmaceutical composition comprising ceftolozane and a stabilizing
effective amount of a stabilizing agent selected from the group
consisting of: sodium chloride, or a non-reducing sugar such as
trehalose and/or sucrose. The pharmaceutical compositions provided
herein are based in part on the surprising discovery that
ceftolozane pharmaceutical compositions comprising these
stabilizing agents demonstrate improved ceftolozane residual rates
(e.g., % ceftolozane remaining after 3 days at 70 degrees C. as
measured by HPLC) and/or chemical stability (e.g., lower reduction
in ceftolozane purity measured by HPLC after 7 days at 60 degrees
C. in a stability test) compared control samples comprising
ceftolozane without a stabilizing agent.
[0142] Accordingly, preferred pharmaceutical antibiotic
compositions can include ceftolozane sulfate and a stabilizing
agent (e.g., 300 to 500 mg of a stabilizing agent per 1,000 mg
ceftolozane active) in a lyophilized unit dosage form (e.g., powder
in a container). The unit dosage form can be dissolved with a
pharmaceutically acceptable carrier (e.g., 0.9% sodium chloride
aqueous isotonic saline and/or water for injection), and then
intravenously administered. In certain ceftolozane compositions,
the stabilizing agent can be selected from the group consisting of:
sodium chloride, lactose, maltose and dextran 40, and/or selected
from the group consisting of: sodium chloride, trehalose and
sucrose.
[0143] An exemplary unit dosage form is described in Example 2, a
white to yellow sterile powder consisting of ceftolozane sulfate
(1147 mg/vial) and tazobactam sodium (537 mg/vial) packaged in
glass vials. The product contains sodium chloride (487 mg/vial) as
a stabilizing agent, citric acid (21 mg/vial), and L-arginine
(approximately 600 g/vial) as excipients. The vial with the unit
dosage form is constituted with 10 mL of sterile water for
injection or 0.9% Sodium Chloride for injection, USP (normal
saline) and gently shaken to dissolve. In another aspect, 10 mL of
5% Dextrose Injection, USP is used. The final volume is
approximately 11.4 mL. The resultant concentration is approximately
132 mg/mL. For preparation of a 1.5 g dose, the entire contents
(approximately 11.4 mL) of the reconstituted vial is removed, for
example, by using a syringe, and added to an infusion bag
containing 100 mL of 0.9% Sodium Chloride for Injection, USP
(normal saline) or 5% Dextrose Injection, USP. In another aspect,
100 mL of sterile water for injection can be used. For preparation
of the 750 mg dose, approximately 5.7 mL of the contents of the
reconstituted vial is withdrawn and added it to an infusion bag
containing 100 mL of 0.9% Sodium Chloride for Injection, USP
(normal saline) or 5% Dextrose Injection, USP. In another aspect,
100 mL of sterile water for injection is used. For preparation of
the 375 mg dose, approximately 2.9 mL of the contents of the
reconstituted vial is withdrawn and added to an infusion bag
containing 100 mL of 0.9% Sodium Chloride for Injection, USP
(normal saline) or 5% Dextrose Injection, USP. In another aspect,
100 mL of sterile water for injection is used. For preparation of
the 150 mg dose, approximately 1.2 mL of the contents of the
reconstituted vial is withdrawn and added it to an infusion bag
containing 100 mL of 0.9% Sodium Chloride for Injection, USP
(normal saline) or 5% Dextrose Injection, USP. In another aspect,
100 mL of sterile water for injection is used.
[0144] Preferably, the ceftolozane/tazobactam pharmaceutical
product does not contain a bacteriostatic preservative. Aseptic
technique is preferably followed in preparing the infusion
solution.
[0145] A therapeutically effective amount of metronidazole or a
pharmaceutically acceptable salt thereof can be administered to a
patient receiving the ceftolozane/tazobactam pharmaceutical
composition for treatment of an intra-abdominal infection,
including a complicated intra-abdominal infection. Metronidazole is
a synthetic nitroimidazole antibacterial agent
2-methyl-5-nitro-1Himidazole-1-ethanol. Metronidazole hydrochloride
(formula III) is a pharmaceutically acceptable salt of
metronidazole that can be intravenously administered.
##STR00003##
[0146] An effective amount of metronidazole is administered in the
treatment methods described herein. Metronidazole is preferably
administered intravenously using a dosage regimen of 15 mg/kg
loading dose (1 gram for a 70 kg adult) followed six hours later by
7.5 mg/kg (500 mg for a 70 kg adult) maintenance dose. Maintenance
doses of 7.5 mg/kg are given intravenously every six hours. The
usual duration of therapy for treating the intra-abdominal
infection can be 4-14 days, possibly 7-10 days. Metronidazole is
preferably administered separately from the
ceftolozane/tazobactam.
[0147] Preferably, the metronidazole is separately intravenously
administered to a patient having, for example, an intra-abdominal
infection. Metronidazole is an antibiotic that can be administered
to patients having intra-abdominal infections, including
peritonitis, intra-abdominal abscess, and liver abscess, caused by
Bacteroides species including the B. fragilis group (B. fragilis,
B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus),
Clostridium species, Eubacterium species, Peptococcus species, and
Peptostreptococcus species.
[0148] Preferably, the metronidazole is intravenously administered
as a pharmaceutically composition of metronidazole hydrochloride
for injection in a sterile 500 mg parenteral unit dosage form of
the synthetic nitroimidazole antibacterial agent
2-methyl-5-nitro-1Himidazole-1-ethanol. The unit dosage form of
metronidazole can be obtained by reconstituting a single-dose vial
of lyophilized metronidazole hydrochloride (e.g., sold under the
brand name FLAGYL I.V.) containing sterile, nonpyrogenic
metronidazole hydrochloride, equivalent to 500 mg metronidazole,
and 415 mg mannitol.
[0149] CXA-201 refers to pharmaceutical compositions comprising
ceftolozane active and tazobactam active in a 2:1 weight ratio.
CXA-201 can be provided in a single vessel (e.g., a bag, vial or
blended composition) or in multiple vessels (e.g., a first
container containing ceftolozane active without tazobactam active,
and a second container containing tazobactam active without
ceftolozane active). The ceftolozane active and tazobactam acid in
CXA-201 can be combined prior to intravenous administration, or
separately intravenously administered. Accordingly, a 1.5 g dose of
CXA-201 comprises a total of 1 g of ceftolozane active and a total
of 0.5 g of tazobactam active. Similarly, a 750 mg dose of CXA-201
comprises a total of 500 mg ceftolozane active and a total of 250
mg of tazobactam active. A 150 mg dose of CXA-201 comprises a total
of 100 mg ceftolozane active and a total of 50 mg of tazobactam
active.
[0150] A preferred CXA-201 pharmaceutical composition is the
ceftolozane/tazobactam composition in Example 2. The C.sub.max and
AUC of this preferred CXA-201 composition increases in proportion
to dose. Plasma levels of this preferred CXA-201 do not increase
appreciably following multiple IV infusions of up to 3.0 g
administered every 8 hours for up to 10 days in healthy adults with
normal renal function. The elimination half-life (t.sub.1/2) of
ceftolozane is independent of dose. The binding of ceftolozane and
tazobactam to human plasma proteins is approximately 16% to 21% and
30%, respectively. The mean (CV %) steady-state volume of
distribution of the CXA-201 composition of Example 2 in healthy
adult males (n=51) following a single 1.5 g IV dose of the CXA-201
composition of Example 2 was 13.5 L (21%) and 18.2 L (25%) for
ceftolozane and tazobactam, respectively, similar to extracellular
fluid volume.
[0151] Ceftolozane is eliminated in the urine as unchanged parent
drug and thus does not appear to be metabolized to any appreciable
extent. The beta-lactam ring of tazobactam is hydrolyzed to form
the pharmacologically inactive, tazobactam metabolite M1.
[0152] The CXA-201 composition of Example 2 and the tazobactam
metabolite M1 are eliminated by the kidneys. Following
administration of a single 1.5 g IV dose of the CXA-201 composition
of Example 2 to healthy male adults greater than 95% of ceftolozane
was excreted in the urine as unchanged parent drug. More than 80%
of tazobactam was excreted as the parent compound with the
remainder excreted as the tazobactam M1 metabolite. After a single
dose of the CXA-201 composition of Example 2, renal clearance of
ceftolozane (3.41-6.69 L/h) was similar to plasma CL (4.10 to 6.73
L/h) and similar to the glomerular filtration rate for the unbound
fraction, suggesting that ceftolozane is eliminated by the kidney
via glomerular filtration.
[0153] The CXA-201 composition of Example 2 and the tazobactam
metabolite M1 are eliminated by the kidneys. The ceftolozane dose
normalized geometric mean AUC increased up to 1.26-fold, 2.5-fold,
and 5-fold in subjects with mild, moderate, and severe renal
impairment, respectively, compared to healthy subjects with normal
renal function. The respective tazobactam dose normalized geometric
mean AUC increased approximately up to 1.3-fold, 2-fold, and
4-fold. To maintain similar systemic exposures to those with normal
renal function, dosage adjustment is required.
[0154] In subjects with ESRD on HD, approximately two-thirds of the
administered CXA-201 composition of Example 2 is removed by HD. The
recommended dose in subjects with ESRD on HD is a single loading
dose of 750 mg of the CXA-201 composition of Example 2 followed by
a 150 mg maintenance dose of the CXA-201 composition of Example 2
administered every 8 hours for the remainder of the treatment
period. On HD days, the dose should be administered at the earliest
possible time following completion of HD.
[0155] CXA-201 is useful for the treatment of complicated
intra-abdominal infections caused by one of the following
Gram-negative and Gram-positive microorganisms: Citrobacter
freundii, Enterobacter cloacae, Escherichia coli, Escherichia coli
CTX-M-14 extended spectrum beta-lactamase producing strains,
Escherichia coli CTX-M-15 extended spectrum beta-lactamase
producing strains, Klebsiella oxytoca, Klebsiella pneumonia,
Klebsiella pneumoniae CTX-M-15 extended spectrum beta-lactamase
producing strains, Proteus mirabilis, Pseudomonas aeruginosa,
Bacteroides fragilis, Bacteroides ovatus, Bacteroides
thetaiotaomicron, Bacteroides vulgatus, Streptococcus anginosus,
Streptococcus constellatus, and Streptococcus salivarius.
[0156] CXA-201 is also useful for the treatment of complicated
urinary tract infection, including where the complicated urinary
tract infection is pyelonephritis, with or without concurrent
bacteremia, or is caused by one of the following Gram-negative
microorganisms: Escherichia coli, Escherichia coli levofloxacin
resistant strains, Escherichia coli CTX-M-14 extended spectrum
beta-lactamase producing strains, Escherichia coli CTX-M-15
extended spectrum beta-lactamase producing strains, Klebsiella
pneumoniae, Klebsiella pneumonia levofloxacin resistant strains,
Klebsiella pneumonia CTX-M-15 extended spectrum beta-lactamase
producing strains, Proteus mirabilis or Pseudomonas aeruginosa.
[0157] CXA-201 can also be used to treat infections caused by the
following bacteria: Gram-negative bacteria--Acinetobacter
baumannii, Burkholderia cepacii, Citrobacter freundii, Citrobacter
koseri, Enterobacter aerogenes, Enterobacter cloacae, Haemophilus
influenza, Moraxella catarrhalis, Morganella morganii, Pantoea
agglomerans, Proteus vulgaris, Providencia rettgeri, Providencia
stuartii, Serratia liquefacians and Serratia marcescens;
Gram-positive aerobic bacteria--Streptococcus agalactiae,
Streptococcus intermedius, Streptococcus pyogenes and Streptococcus
pneumonia; Anaerobic microorganisms such as Fusobacterium spp, and
Prevotella spp.
[0158] In one embodiment, use of a ceftolozane and tazobactam in
one or more pharmaceutical compositions for treating a patient in
need thereof is disclosed, comprising administering a dose of
ceftolozane and tazobactam of the ceftolzoane and tazobactam, with
or without a loading dose, in amounts and at a dosing interval
effective to provide at least an unbound concentration of
ceftolozane of at least 8 micrograms/mL for at least 30% of the
time between successive treatment days and unbound tazobactam of
about 1 microgram/mL for at least 20% of the time and about 0.5
microgram/mL for about or higher than 50% of the time.
[0159] In another embodiment, use of a pharmaceutical composition
comprising ceftolozane active and tazobactam active in a 2:1 weight
ratio, for treating an infection in a patient is disclosed,
comprising administering to the patient a dose of the
pharmaceutical composition, with or without a loading dose, in
therapeutically effective amounts and at a dosing interval
therapeutically effective to provide at least an unbound
concentration of ceftolozane of at least 8 micrograms/mL in the
patient for at least 30% of the time between successive treatment
days and unbound tazobactam of about 1 microgram/mL for at least
20% of the time and about 0.5 microgram/mL for about or higher than
50% of the time during the duration of treatment.
[0160] In an embodiment, a pharmaceutical composition comprising
ceftolozane active and tazobactam active in a 2:1 weight ratio is
administered to a patient with impaired renal function in
accordance with the Tables below:
Dosage of CXA-201 in Patients with Renal Impairment
TABLE-US-00004 Estimated CrCL (mL/min)* Recommended Dosage Regimen
for CXA-201** 30 to 50 750 mg intravenously every 8 hours 15 to 29
375 mg intravenously every 8 hours End stage renal A single loading
dose of 750 mg followed by disease (ESRD) on a 150 mg maintenance
dose administered hemodialysis (HD) every 8 hours for the remainder
of the treatment period (on hemodialysis days, the dose should be
administered at the earliest possible time following completion of
dialysis) *CrCL estimated using Cockcroft-Gault formula **All doses
of CXA-201 are administered over 1 hour
Dosage of Ceftolozane/Tazobactam in Patients with Renal
Impairment
TABLE-US-00005 Estimated CrCL (mL/min)* Recommended Dosage Regimen
** 30 to 50 500 mg ceftolozane active and 250 mg tazobactam active
intravenously administered in a single or separate pharmaceutical
compositions every 8 hours 15 to 29 250 mg ceftolozane active and
125 mg tazobactam active administered in a single or separate
pharmaceutical compositions intravenously every 8 hours End stage
renal disease (ESRD) A single loading dose of 500 mg ceftolozane
active and 250 mg on hemodialysis (HD) tazobactam active
administered in a single or separate pharmaceutical compositions;
followed by a 100 mg ceftolozane active and 50 mg tazobactam active
maintenance dose administered in a single or separate
pharmaceutical compositions every 8 hours for the remainder of the
treatment period (on hemodialysis days, the dose should be
administered at the earliest possible time following completion of
dialysis) *CrCL estimated using Cockcroft-Gault formula ** All
doses of CXA-201 are administered over 1 hour The invention is
illustrated by the following non-limiting examples.
EXAMPLES
Example 1: Manufacturing of Combination Product (Tazobactam and
Ceftolozane) by Blending
[0161] CXA-201 compositions can be obtained by uniformly blending
lyophilized ceftolozane or pharmaceutically acceptable salt thereof
with lyophilized tazobactam in amounts providing a 2:1 weight ratio
between the amount of ceftolozane active and tazobactam active in
the blended CXA-201 composition. The ceftolozane can be ceftolozane
sulfate lyophilized with one or more excipients without tazobactam.
The tazobactam can be lyophilized with one or more excipients
(e.g., sodium bicarbonate) without ceftolozane.
Example 2: Components of a Representative CXA-201 Composition
[0162] An example of a batch formulae for the RSD for each of
ceftolozane and tazobactam content assay was no greater than 2% and
the RSD for the ratio of ceftolozane/tazobactam was no greater than
2.2%.
[0163] Ceftolozane composition (compounding of ceftolozane
substance with excipients such as citric acid, sodium chloride, and
L-arginine followed by sterile lyophilization) is found below in
Table 5.
TABLE-US-00006 TABLE 5 Batch Formula for Ceftolozane Composition
Target Composition Amount per Batch (kg) Component mg/g 1 2
Ceftolozane Sulfate.sup.1) 172.1 114.0 202.6 Citric Acid,
Anhydrous, 3.2 2.1 3.7 USP Sodium Chloride, USP 73.1 48.3 86.0
L-Arginine, USP ~90 QS to 59.7 106.0 achieve target pH.sup.2) Water
for Injection, USP QS to 1000 QS QS Total Batch Size 660 1175
.sup.1)Ceftolozane sulfate was charged based on its measured
potency to obtain 150 mg free base/g solution. .sup.2)L-arginine
was added as needed to obtain pH 6.5 .+-. 0.5 in the bulk solution;
90 mg per gram solution was considered a representative amount.
[0164] An example of a batch formula for the ceftolozane/tazobactam
drug product is presented in Table 6 below.
TABLE-US-00007 TABLE 6 Batch Formula Ceftolozane/Tazobactam Drug
Product Amount per Amount per Component container, mg Batch, kg
Ceftolozane 2255 112.8 composition1) Tazobactam2) 537 26.9
Nitrogen, NF3) -- -- Total 2792 139.7 Total Batch Size, kg 139.7
Total container Quantity 50,000
[0165] The target fill for ceftolozane was 1000 mg free base, added
to the container as the composition. The amount 2255 mg was based
on 100% theoretical potency of the composition. Actual weight will
vary based on composition measured potency. The target fill for
tazobactam is 500 mg free acid, added to the container as its
sodium salt form. The amount 537 mg was based on 100% theoretical
potency. Nitrogen was used as a processing aid to blanket
containers after powder filling and prior to insertion of stopper.
The unit composition of a dosage for reconstitution is described in
Table 7.
TABLE-US-00008 TABLE 7 Unit Compositions of Ceftolozane/Tazobactam
for Injection, 1000 mg/500 mg Nominal Composition Component
Function mg per container Ceftolozane Ceftolozane Active 1147
composition.sup.1) Sulfate Citric Acid, Chelating Agent 21
Anhydrous Sodium Stabilizing Agent 487 Chloride L-Arginine
Alkalizing Agent 600.sup.2) Q.S. for pH adjustment Tazobactam
Sodium.sup.3) Active 537 Nitrogen Processing Aid.sup.(a) Q.S. Total
Weight 2792 .sup.1)Actual amount of ceftolozane composition will
vary based on the measured potency. Ceftolozane sulfate, 1147 mg,
corresponds to 1000 mg ceftolozane free base. .sup.2)L-arginine was
added as needed to achieve pH 6.5 .+-. 0.5; 600 mg per container
was considered a representative total amount. .sup.3)Actual weight
of tazobactam sodium will vary based on the measured potency.
Tazobactam sodium 537 mg, corresponds to 500 mg tazobactam free
acid. 4) Nitrogen blanket was applied after powders are dispensed
to the container and prior to insertion of stopper.
Example 3: Summary of CXA-201 in Phase 3 Comparator-Controlled
Clinical Trials of Complicated Intra-Abdominal Infections and
Complicated Urinary Tract Infections
[0166] The CXA-201 of Example 2 was evaluated in Phase 3
comparator-controlled clinical trials of complicated
intra-abdominal infections and complicated urinary tract
infections, which included a total of 1015 patients treated with
CXA-201 and 1032 patients treated with comparator (levofloxacin or
meropenem) for up to 14 days. The most common adverse reactions
(.gtoreq.5% in either indication) occurring in patients receiving
CXA-201 were nausea, headache and diarrhea. Table 3 lists adverse
reactions occurring in .gtoreq.1.0% of patients receiving CXA-201
in Phase 3 clinical trials.
TABLE-US-00009 TABLE 3 Adverse Reactions Occurring in .gtoreq.1.0%
of Patients Receiving CXA-201 in Phase 3 Clinical Trials
Complicated Complicated Urinary Tract Intra-abdominal Infections,
Including Infections Pyelonephritis CXA-201 Meropenem CXA-201
Levofloxacin Preferred Term (N = 482) (N = 497) (N = 533) (N = 535)
Nausea 38 (7.9) 29 (5.8) 15 (2.8) 9 (1.7) Headache 12 (2.5) 9 (1.8)
31 (5.8) 26 (4.9) Diarrhea 30 (6.2) 25 (5.0) 10 (1.9) 23 (4.3)
Constipation 9 (1.9) 6 (1.2) 21 (3.9) 17 (3.2) Vomiting 16 (3.3) 20
(4.0) 6 (1.1) 6 (1.1) ALT increased 7 (1.5) 5 (1.0) 9 (1.7) 5 (0.9)
AST increased 5 (1.0) 3 (0.6) 9 (1.7) 5 (0.9) Abdominal pain 6
(1.2) 2 (0.4) 4 (0.8) 2 (0.4) .sup.aThe CXA-201 dose was 1.5 g IV
every 8 hours, adjusted to match renal function where appropriate.
In the complicated intra-abdominal infection studies CXA-201 was
given in conjunction with metronidazole.
[0167] Treatment discontinuation due to adverse events occurred in
2.0% (20/1015) of patients receiving CXA-201 and 1.9% (20/1032) of
patients receiving comparator drugs. Renal impairment (including
the terms renal impairment, renal failure, and renal failure acute)
was the only adverse event that led to discontinuation of treatment
in >1 subject receiving CXA-201.
Overdosage
[0168] In the event of overdose, CXA-201 should be discontinued and
general supportive treatment given. CXA-201 can be removed by
hemodialysis. Approximately 66% of ceftolozane, 56% of tazobactam,
and 51% of the tazobactam metabolite M1 were removed by dialysis.
However, no information is available on the use of hemodialysis to
treat overdosage. The highest single dose of CXA-201 received in
clinical trials was 4.5 g (comprised of 3.0 g of ceftolozane and
1.5 g of tazobactam); at this dosage no adverse pharmacological
effects or increased safety risks have been observed.
Pharmacokinetics
[0169] The mean pharmacokinetic parameters of CXA-201 in healthy
adults with normal renal function after single and multiple 1-hour
IV infusions of 1.5 g CXA-201 administered every 8 hours are
summarized in Table 4. Pharmacokinetic parameters were similar for
single and multiple dose administration.
TABLE-US-00010 TABLE 4 Mean (CV %) Plasma Pharmacokinetic
Parameters of CXA-201 After Single and Multiple 1.5 g Intravenous
1-hour Infusions of CXA-201 Every 8 Hours in Healthy Adults
Ceftolozane/Tazobactam (1.5 g every 8 hours) Ceftolozane Tazobactam
Day 1 Day 10 Day 1 Day 10 PK parameters (n = 9).sup.a (n = 10) (n =
9).sup.a (n = 10) C.sub.max (.mu.g/mL) 69.1 (11) 74.4 (14) 18.4
(16) 18.0 (8) t.sub.max (h).sup.b 1.02 (1.01, 1.1) 1.07 (1.0, 1.1)
1.02 (0.99, 1.03) 1.01 (1.0, 1.1) AUC (.mu.g h/mL).sup.c 172 (14)
182 (15) 24.4 (18) 25.0 (15) t.sub.1/2 (h) 2.77 (30) 3.12 (22) 0.91
(26).sup.d 1.03 (19) .sup.aN = 9, one outlier subject excluded from
descriptive statistics .sup.bMedian (minimum, maximum) presented
.sup.cAUC for Day 1 = AUC.sub.last and AUC for Day 10 = steady
state AUC (AUC.sub..tau., ss) .sup.dN = 8, one subject excluded
from descriptive statistics as the concentration-time profile did
not exhibit a terminal log-linear phase and t.sub.1/2 could not be
calculated
[0170] The C.sub.max and AUC of CXA-201 increase in proportion to
dose. Plasma levels of CXA-201 do not increase appreciably
following multiple IV infusions of up to 3.0 g administered every 8
hours for up to 10 days in healthy adults with normal renal
function. The elimination half-life (t.sub.1/2) of ceftolozane is
independent of dose.
Distribution
[0171] The binding of ceftolozane and tazobactam to human plasma
proteins is approximately 16% to 21% and 30%, respectively. The
mean (CV %) steady-state volume of distribution of CXA-201 in
healthy adult males (n=51) following a single 1.5 g IV dose of
CXA-201 was 13.5 L (21%) and 18.2 L (25%) for ceftolozane and
tazobactam, respectively, similar to extracellular fluid
volume.
Metabolism
[0172] Ceftolozane is eliminated in the urine as unchanged parent
drug and thus does not appear to be metabolized to any appreciable
extent. The beta-lactam ring of tazobactam is hydrolyzed to form
the pharmacologically inactive, tazobactam metabolite M1.
Excretion
[0173] CXA-201 and the tazobactam metabolite M1 are eliminated by
the kidneys. Following administration of a single 1.5 g IV dose of
CXA-201 to healthy male adults greater than 95% of ceftolozane was
excreted in the urine as unchanged parent drug. More than 80% of
tazobactam was excreted as the parent compound with the remainder
excreted as the tazobactam M1 metabolite. After a single dose of
CXA-201, renal clearance of ceftolozane (3.41-6.69 L/h) was similar
to plasma CL (4.10 to 6.73 L/h) and similar to the glomerular
filtration rate for the unbound fraction, suggesting that
ceftolozane is eliminated by the kidney via glomerular
filtration.
Specific Populations
Renal Impairment
[0174] Because CXA-201 and the tazobactam metabolite M1 are
eliminated primarily by the kidneys, a dosage adjustment is
required for patients whose creatinine clearance is <50
mL/min.
[0175] The ceftolozane dose normalized geometric mean AUC increased
up to 1.26-fold, 2.5-fold, and 5-fold in subjects with mild,
moderate, and severe renal impairment, respectively, compared to
healthy subjects with normal renal function. The respective
tazobactam dose normalized geometric mean AUC increased
approximately up to 1.3-fold, 2-fold, and 4-fold. To maintain
similar systemic exposures to those with normal renal function,
dosage adjustment is required.
[0176] In subjects with ESRD on HD, approximately two-thirds of the
administered CXA-201 dose is removed by HD. The recommended dose in
subjects with ESRD on HD is a single loading dose of 750 mg CXA-201
followed by a 150 mg maintenance dose of CXA-201 administered every
8 hours for the remainder of the treatment period. On HD days, the
dose should be administered at the earliest possible time following
completion of HD, as summarized in the Table below:
Dosage of CXA-201 in Patients with Renal Impairment
TABLE-US-00011 Estimated CrCL (mL/min)* Recommended Dosage Regimen
for CXA-201** 30 to 50 750 mg intravenously every 8 hours 15 to 29
375 mg intravenously every 8 hours End stage renal A single loading
dose of 750 mg followed by a disease (ESRD) on 150 mg maintenance
dose administered every hemodialysis (HD) 8 hours for the remainder
of the treatment period (on hemodialysis days, the dose should be
administered at the earliest possible time following completion of
dialysis) *CrCL estimated using Cockcroft-Gault formula **All doses
of CXA-201 are administered over 1 hour
Example 4: Clinical Trials of CXA-201 in Patients with Complicated
Intra-Abdominal Infections
[0177] A total of 979 adults hospitalized with complicated
intra-abdominal infections were randomized and received study
medications in a multinational, double-blind study comparing
CXA-201 (1.5 g IV every 8 hours) plus metronidazole (500 mg IV
every 8 hours) to meropenem (1 g IV every 8 hours) for 4 to 14 days
of therapy. Complicated intra-abdominal infections included
appendicitis, cholecystitis, diverticulitis, gastric/duodenal
perforation, perforation of the intestine, and other causes of
intra-abdominal abscesses and peritonitis. The primary efficacy
endpoint was clinical response at the test-of-cure (TOC) visit in
the microbiological intent-to-treat (MITT) population, which
included all patients who had at least 1 baseline intra-abdominal
pathogen. The key secondary efficacy endpoint was clinical response
at the TOC visit in the microbiologically evaluable (ME)
population, which included all protocol-adherent MITT patients.
[0178] The MITT population consisted of 806 patients; the median
age was 52 years and 57.8% were male. Diffuse peritonitis at
baseline, a marker of severity, was present in 34.2% of patients.
Laparotomy was the initial intra-abdominal intervention in 67.7% of
patients, and ESBL-producing Enterobacteriaceae were identified in
58 (7.2%) patients at baseline.
[0179] CXA-201 plus metronidazole showed non-inferiority to
meropenem with regard to clinical cure rates at the TOC visit in
both the MITT and ME populations. Clinical cure rates at the TOC
visit are displayed by patient population in Table 8. Clinical cure
rates at the TOC visit by pathogen in the ME population are
presented in Table 9.
TABLE-US-00012 TABLE 8 Clinical Cure Rates in a Phase 3 Study of
Complicated Intra-Abdominal Infections CXA-201 plus Percentage
Analysis metronidazole.sup.a Meropenem.sup.b Difference Population
n/N (%) n/N (%) (95% CI).sup.c MITT 323/389 (83.0) 364/417 (87.3)
-4.2 (-8.91, 0.54) ME 259/275 (94.2) 304/321 (94.7) -1.0 (-4.52,
2.59) .sup.aCXA-201 1.5 g IV every 8 hours + metronidazole 500 mg
IV every 8 hours. .sup.b1 g IV every 8 hours. .sup.cThe 95% CI was
calculated using the Newcombe method with minimum risk weights
TABLE-US-00013 TABLE 9 Per Pathogen Clinical Cure Rates in a Phase
3 Study of Complicated Intra-abdominal Infections (ME Population)
Pathogen Category CXA-201 plus Baseline Intra-abdominal
metronidazole Meropenem Pathogen n/N (%) n/N (%) Aerobic
Gram-negative 238/252 (94.4) 273/291 (93.8) Escherichia coli
197/208 (94.7) 216/231 (93.5) Escherichia coli 14/14 (100) 18/20
(90.0) (EBSL-producing) Escherichia coli 9/9 (100) 7/9 (77.8)
(CTX-M-14/15 ESBL-producing) Klebsiella pneumonia 28/30 (93.3)
22/25 (88.0) Klebsiella pneumoniae 7/8 (87.5) 3/4 (75.0)
(ESBL-producing) Klebsiella pneumoniae 5/5 (100) 0/1 (0) (CTX-M-15
ESBL-producing) Pseudomonas aeruginosa 26/26 (100) 27/29 (93.1)
Enterobacter cloacae 19/22 (86.4) 22/22 (100) Klebsiella oxytoca
12/12 (100) 21/22 (95.5) Proteus mirabilis 10/11 (90.9) 9/10 (90.0)
Aerobic Gram-positive 153/168 (91.1) 170/185 (91.9) Streptococcus
anginosus 25/30 (83.3) 23/23 (100) Streptococcus constellatus 17/18
(94.4) 20/23 (87.0) Streptococcus salivarius 9/10 (90.0) 8/8 (100)
Anaerobic Gram-negative 104/109 (95.4) 132/137 (96.4) Bacteroides
fragilis 39/41 (95.1) 56/57 (98.2) Bacteroides ovatus 36/37 (97.3)
42/42 (100) Bacteroides thetaiotaomicron 20/20 (100) 40/43 (93.0)
Bacteroides vulgatus 12/13 (92.3) 21/22 (95.5)
Example 5 Clinical Trials with CXA-201 in Patients with Complicated
Urinary Tract Infections, Including Pyelonephritis
[0180] A total of 1068 adults hospitalized with complicated urinary
tract infections (including pyelonephritis) were randomized and
received study medications in a multinational, double-blind study
comparing CXA-201 (1.5 g IV every 8 hours) to levofloxacin (750 mg
IV once daily) for 7 days of therapy. The primary efficacy endpoint
was the composite microbiological and clinical cure response at the
test-of-cure (TOC) visit in the microbiologically modified
intent-to-treat (mMITT) population, which included all patients who
received study medication and had at least 1 baseline uropathogen.
The key secondary efficacy endpoint was the composite
microbiological and clinical cure response at the TOC visit in the
microbiologically evaluable (ME) population, which included
protocol-adherent mMITT patients with a urine culture at the TOC
visit.
[0181] The mMITT population consisted of 800 patients with cUTI,
including 656 (82%) with pyelonephritis, 34.3% had mild or moderate
renal impairment, and 24.9% were aged .gtoreq.65 years. The median
age in this population was 50.5 years and 74% were female (FIG.
1A).
[0182] Most patients in the mMITT population had a monomicrobial
infection (97.0%), most commonly due to E. coli (78.6%). Other
baseline uropathogens included Klebsiella pneumoniae (7.3%),
Proteus mirabilis (3.0%), and P. aeruginosa (2.9%). In the mMITT
population, 26.5% (212/800) of patients had levofloxacin-resistant
uropathogens and 14.8% (118/800) had ESBL-producing
Enterobacteriaceae organisms isolated from the baseline urine
culture.
[0183] The results of baseline susceptibility testing to both study
drugs are provided in FIG. 1B. In the mMITT population, 96.6% of
all gram-negative pathogens isolated at baseline were susceptible
to ceftolozane/tazobactam (using a breakpoint of .ltoreq.8 mg/1)
compared with 70.7% susceptible to levofloxacin using CLSI
(Clinical and Laboratory Standards Institute) criteria.11 Of note,
99.7% of E. coli isolates were susceptible to
ceftolozane/tazobactam, regardless of ESBL phenotype (minimum
inhibitory concentration required to inhibit the growth of 50%/90%
of organisms [MIC50/90] 0.25/0.5 mg/1) compared with 74.1% for
levofloxacin (MIC50/90 0.03/>4 mg/1).
[0184] CXA-201 was superior to levofloxacin with regard to the
composite microbiological and clinical cure rates at the TOC visit
in both the mMITT and ME populations (Table 10 and FIG. 1C).
[0185] Microbiological eradication rates at the TOC visit by
pathogen in the ME population are presented in Table 11A.
[0186] In patients with levofloxacin-resistant pathogens at
baseline, CXA-201 was superior to levofloxacin with regards to
composite cure rates in the mMITT population, 60/100 (60%) in the
CXA-201 treatment arm and 44/112 (39.3) in the levofloxacin
treatment arm (95% CI: 20.7) (Table 11B).
TABLE-US-00014 TABLE 10 Composite Microbiological and Clinical Cure
Rates in a Phase 3 Study of Complicated Urinary Tract Infections
Treatment Analysis CXA-201.sup.a Levofloxacin.sup.b Difference
Population n/N (%) n/N (%) (99% CI).sup.c mMITT 306/398 (76.9)
275/402 (68.4) 8.5 (0.36, 16.46) ME 284/341 (83.3) 266/353 (75.4)
8.0 (0.01, 15.84) .sup.a1.5 g IV every 8 hours. .sup.b750 mg IV
once daily. .sup.cThe 99% CI was based on the stratified Newcombe
method.
TABLE-US-00015 TABLE 11A Per Pathogen Microbiological Eradication
Rates in a Phase 3 Study of Complicated Urinary Tract Infections
(ME Population) Organism Group CXA-201 Levofloxacin Pathogen n/N
(%) n/N (%) Aerobic Gram-negative 287/323 (88.9) 263/340 (77.4)
Escherichia coli 237/262 (90.5) 226/284 (79.6) Escherichia coli
27/36 (75) 18/36 (50) (ESBL-producing) Escherichia coli 20/27
(74.1) 13/25 (52.0) (CTX-M-14/15 ESBL producing) Klebsiella
pneumoniae 21/25 (84.0) 14/23 (60.9) Klebsiella pneumoniae 7/10
(70) 2/7 (29) (ESBL-producing) Klebsiella pneumoniae 5/8 (62.5) 1/4
(25.0) (CTX-M-15 ESBL producing) Proteus mirabilis 10/10 (100) 8/11
(72.7) Pseudomonas aeruginosa 6/7 (85.7) 7/12 (58.3)
TABLE-US-00016 TABLE 11B Per Pathogen Microbiological Eradication
Rates vs Levofloxacin in the mMITT and ME Populations Outcomes in
the Ceftolozane/ Levofloxacin-resistant tazobactam Levofloxacin
Difference Population at TOC Population % (n/N) % (n/N) % (95% CI)
Composite Cure Rate mMITT 60.0 (60/100) 39.3 (44/112) 20.7 (7.23 to
33.17) ME 64.0 (57/89) 43.4 (43/99) 20.6 (6.33 to 33.72)
Per-pathogen Microbiological ME Eradication Rate Enterobacteriaceae
71.4 (55/77) 45.2 (38/84) 26.2 (10.96 to 39.72) Escherichia coli
72.9 (43/59) 44.1 (30/68) 28.8 (11.59 to 43.55) Klebsiella
pneumoniae 81.8 (9/11) 30.0 (3/10) 51.8 (9.50 to 75.05) Pseudomonas
aeruginosa 100.0 (3/3) 37.5 (3/8) 62.5 (-2.09 to 86.32)
[0187] In the mMITT population, composite cure rates in patients
with concurrent bacteremia were 23/29 (79.3%) for CXA-201 and 19/33
(57.6%) for levofloxacin (FIG. 1D).
[0188] The incidence of adverse events, including serious adverse
events, was low and comparable in both treatment groups (FIGS. 1E
and 1F). Adverse events occurred in 34.7% (185/533) and 34.4%
(184/535) of patients in the ceftolozane/tazobactam and
levofloxacin groups, respectively. The most common adverse events
were headache (5.8% and 4.9%) and gastrointestinal symptoms (11.8%
and 11.4%) for ceftolozane/tazobactam and levofloxacin,
respectively. The majority of adverse events were mild to moderate
in severity, and the incidence of treatment-limiting adverse events
was <2% in both treatment groups. Epidemiology and
susceptibility of organisms isolated from patients with cUTI.
Methods
[0189] 764 isolates of Gram-negative aerobic organisms were
isolated from 800 patients in the microbiological modified
intent-to-treat population (enrolled in 20 countries in Eastern
Europe, North America, South America and 5 countries outside of
these regions). Susceptibility (S) testing was performed with
ceftolozane/tazobactam at a fixed 4 .mu.g/mL of tazobactam and 10
antibiotic comparators using CLSI broth microdilution methods. ESBL
enzymes were identified by PCR.
Results
[0190] The activity of ceftolozane/tazobactam was similar across
geographic regions with the exception of decreased activity against
a subset of P. aeruginosa isolates from E. Europe possessing
carbapenemases. Potent activity was observed against isolates of
Enterobacteriaceae and P. aeruginosa, with limited Enterococcus
spp. activity. E. coli was the most common pathogen (78.6%) and
ceftolozane/tazobactam was the most active beta-lactam tested
against E. coli (99.7% inhibited at .ltoreq.8 .mu.g/mL), including
CTX-M-14/15+isolates (MIC90, 1 .mu.g/mL). The majority (60.0%) of
P. aeruginosa isolates were inhibited at ceftolozane/tazobactam
concentrations .ltoreq.8 .mu.g/mL while these isolates exhibited
moderate susceptibility to imipenem (IMI, 45.0%), ceftazidime (CAZ;
40.0%), cefepime (FEP, 50.0%), piperacillin/tazobactam (P/T;
40.0%), levofloxacin (LVX; 35.0%), and amikacin (AMI; 55.0%).
Against Klebsiella pneumoniae (KPN), ceftolozane/tazobactam
activity was improved relative to that of CAZ (87.3% vs 58.2%
inhibited at .ltoreq.8 .mu.g/mL respectively) including
CTX-M-15+isolates of KPN (73.3% inhibited at .ltoreq.8 .mu.g/mL)
while the activity of comparators except colistin and IMI was
greatly reduced.
Example 6: ESBL-Producing Strains of Gram-Negative Pathogens in the
Phase 3 Clinical Trials
[0191] The clinical response rates of CXA-201 and comparators
against E. coli and K. pneumoniae strains producing CTX-M-14/15
ESBLs in the Phase 3 clinical trials are shown in Table 12.
TABLE-US-00017 TABLE 12 Clinical Cure Rates by ESBL Status from the
Phase 3 Clinical Trials (ME Population) CXA-201.sup.a All
Comparators.sup.b Pathogen n/N (%) n/N (%) Escherichia coli 452/470
(96.2) 483/515 (93.8) Escherichia coli 49/50 (98.0) 48/56 (87.5)
(ESBL-producing) Escherichia coli 35/36 (97.2) 28/34 (82.4)
(CTX-M-14/15 ESBL-producing) Klebsiella pneumoniae 51/55 (92.7)
41/48 (85.4) Klebsiella pneumonia 17/18 (94.4) 8/11 (72.7)
(ESBL-producing) Klebsiella pneumoniae 13/13 (100) 2/5 (40.0)
(CTX-M-15 ESBL-producing) .sup.aThe CXA-201 dose received was 1.5 g
IV every 8 hours. In the complicated intra-abdominal infection
studies CXA-201 was combined with metronidazole. .sup.bComparators
included meropenem 1 g IV every 8 hours in the Phase 3 complicated
intra-abdominal infection trial and levofloxacin 750 mg IV every 24
hours in the Phase 3 complicated urinary tract infection
trials.
Example 7: Population Pharmacokinetics of Ceftolozane/Tazobactam
(as CXA-201) in Healthy Volunteers, Subjects with Varying Degrees
of Renal Function and Patients with Bacterial Infections
[0192] Ceftolozane/tazobactam is a novel anti-pseudomonal
cephalosporin with a well-established .beta.-lactamase inhibitor.
In vitro studies have demonstrated potent activity against
Pseudomonas aeruginosa, including drug-resistant strains, and other
Gram-negative pathogens including most common extended-spectrum
.beta.-lactamase (ESBL)--producing Enterobacteriaceae. Ceftolozane
exerts its bactericidal activity by inhibition of essential
penicillin-binding proteins (PBPs). Tazobactam is an inhibitor of
most common class A .beta.-lactamases and some class C
.beta.-lactamases that, by binding to the active site of these
enzymes, protects ceftolozane from hydrolysis and broadens coverage
to include most ESBL-producing Enterobacteriaceae. In addition,
ceftolozane/tazobactam has the most potent anti-pseudomonal
activity among currently available cephalosporins and is minimally
affected by AmpC overexpression, increases in efflux mechanisms,
and porin deficiencies. Ceftolozane/tazobactam is currently in
clinical development for the treatment of complicated urinary tract
infections (cUTIs), complicated intra-abdominal infections (cIAIs),
and nosocomial pneumonia.
[0193] The pharmacokinetic (PK) profile of ceftolozane/tazobactam
has been studied in several preclinical and clinical studies. In
healthy volunteers the PK of ceftolozane/tazobactam is
dose-proportional and linear across a wide range of doses (up to
3000 mg/1500 mg as a single dose) with a terminal elimination
half-life (t.sub.1/2.beta.) of approximately 2.5 hours for
ceftolozane and 1 hour for tazobactam. Both ceftolozane and
tazobactam are primarily excreted in the urine; ceftolozane almost
completely in the urine as unchanged parent drug suggesting minimal
metabolism, and tazobactam with 80% as the unchanged parent drug
and the remaining as inactive M1 metabolite that is formed via
hydrolysis of tazobactam. There is no drug-drug interaction between
ceftolozane and tazobactam when co-administered.
[0194] PK/pharmacodynamic (PD) models are of particular importance
for describing the efficacy and safety of anti-bacterials and for
identifying patient covariates that need to be taken into account
for determining optimal dose strategies and evaluating
exposure-response relationships. The aims of this analysis were:
(1) to develop a population PK model for ceftolozane/tazobactam in
healthy subjects and in target populations such as patients with
renal impairment and complicated bacterial infections; (2) to
identify intrinsic and extrinsic determinants of variability
(covariates) in the PK of ceftolozane and tazobactam. The analysis
was performed using published guidance from the US Food and Drug
Administration (FDA) and European Medicines Agency (EMA).
Materials and Methods
[0195] A population-PK analysis was performed on plasma ceftolozane
and tazobactam concentration-time data from adult subjects enrolled
in 10 studies. Subjects were included from multiple sites and all
studies were performed in accordance with the International
Conference on Harmonization guidelines on good clinical practice
and the Declaration of Helsinki. An investigational review board
approved the study protocols at each site.
[0196] Serum concentration data were analyzed from 5 studies in
healthy volunteers (n=184), 3 studies in subjects with varying
degrees of renal impairment (n=42), and 2 phase 2 studies in
patients with bacterial infections (cUTIs [n=73] and cIAIs [n=77]).
In all studies, ceftolozane was administered as a 1-hour
intravenous infusion either alone or in combination with tazobactam
at a fixed 2:1 ratio (ceftolozane:tazobactam). Healthy volunteers
received single or multiple (every 8 hours [q8h] or every 12 hours
[q12h]) doses of ceftolozane alone (250, 500, 1000, 1500, 2000 mg
or ceftolozane/tazobactam (500/250, 1000/500, 1500/750, 2000/1000,
3000/1500) (See Example 13) with sampling periods up to 24 hours
following infusion (FIG. 2). Subjects with mild (creatinine
clearance [CrCL] of .gtoreq.50 to .ltoreq.90 mL/min) or moderate
(CrCL of .gtoreq.30 to <50 mL/min) renal impairment received a
single dose of ceftolozane/tazobactam 1000/500 mg, with sampling up
to 36 hours. Subjects with severe renal impairment (CrCL of
.gtoreq.15 to <30 mL/min) received a single dose of
ceftolozane/tazobactam 500/250 mg, with sampling up to 48 hours. In
the phase 2 trials, cUTI patients received ceftolozane alone 1000
mg (q8h) and cIAI patients received ceftolozane/tazobactam 1000/500
mg (q8h).
[0197] All subjects who received at least 1 dose of study
medication and had at least 1 measurement of ceftolozane or
tazobactam were included (N=376). Plasma concentrations of
ceftolozane and tazobactam were determined by a validated
liquid-chromatography-tandem mass spectrometry assay
(MicroConstants, Inc., San Diego, Calif.) described previously.
Concentrations below the limit of quantitation (BLQ), as defined
previously, were considered as missing. No substitutions were made
to account for these missing data points.
Population Pharmacokinetic Analysis
[0198] Base model development. The model was developed in 2 stages:
a preliminary PK model was developed based on datasets from 3
studies. In the current analysis, the structural model was refined
using the PK data from 10 studies (including patients with cUTI or
cIAI) and the covariate analysis repeated. The results based on
this revised model are presented here. A nonlinear mixed-effects
model was developed with Phoenix.RTM. NLME.TM. software, version
1.2, 2012 (Certara L.P. Pharsight, St. Louis, Mo.) using
first-order maximum likelihood estimation, and a 2-compartment
structure model was fitted to the plasma concentration time data.
The First Order Conditional Estimation-Extended Least Squares
(FOCE-ELS) engine was used for model fitting. The software R (R
Foundation for Statistical Computing, Vienna, Austria, 2013) was
used to generate tables of post hoc PK parameters and descriptive
statistics.
[0199] Models had the form:
C.sub.p.sub.ij=C(D.sub.i,t.sub.j,.theta..sub.i)+.epsilon..sub.ij
.theta..sub.i=(.theta..sub.i1, . . . ,.theta..sub.im)
[0200] where C.sub.pij is the concentration at j.sup.th time for
subject i, D.sub.i represents dosing history for subject i,
.theta..sub.i is the vector of m model parameters for subject i,
and .epsilon..sub.ij is random error associated with a
concentration at the j.sup.th time (t.sub.j) for subject i.
[0201] A variance component, which assumed a log-normal
distribution of PK parameters, was used to characterize the between
subject variability (BSV) and between occasion variability (BOV) in
model parameters using the following equation:
.theta..sub.in=.theta..sub.TVn exp(.eta..sub.in)
(.eta..sub.1 . . . .eta..sub.m).about.MVN(0,.OMEGA.)
[0202] Where .theta..sub.TVn is the population typical value for
the n.sup.th PK parameter (e.g., clearance), and .eta..sub.in is
the individual random effect (.eta. is referred to as ETA
hereafter) and occasion random effect on the n.sup.th parameter for
subject i that jointly follow a multivariate normal distribution
(MVN) with mean zero and variance .OMEGA..
[0203] Residual unexplained variability was modelled using additive
.+-.proportional error models, including:
y.sub.ij=y{circumflex over (
)}.sub.ij*(1+.epsilon..sub.1ij)+.epsilon..sub.2ij
[0204] where y.sub.ij (observed) and y{circumflex over ( )}.sub.ij
(predicted) represent the j.sup.th plasma drug concentration for
the i.sup.th subject, and .epsilon. is the random residual
variability. Each .epsilon. (.epsilon..sub.1 and .epsilon..sub.2)
is normally distributed with mean 0 and variance .sigma..sup.2.
Sources of Variability and Covariate Analysis
[0205] Sources of variability, that may affect drug exposure, were
identified using correlation plots of individual random effects
(ETA with mean 0 and estimated variance co.sup.2) of parameters
such as systemic clearance (CL) and central volume of distribution
(Vc) versus covariates. Extrinsic covariates analyzed included dose
levels, drug-drug interactions between ceftolozane and tazobactam,
and disease status (bacterial infections). Intrinsic covariates
analyzed included body weight, age, sex, ethnicity, and baseline
calculated CrCL). The CrCL was estimated using the Cockcroft-Gault
formula:
CrCL={[(140-Age).times.WT]/S.sub.Cr}
[0206] where CrCL is creatinine clearance (ml/min), age is in
years, WT is actual body weight (kg), and S.sub.Cr is serum
creatinine (mg/dl); for female subjects the value was multiplied by
a factor of 0.85. Renal impairment was categorized as normal (CrCL
.gtoreq.90 mL/min), mild (CrCL .gtoreq.50-<90 mL/min), moderate
(CrCL .gtoreq.30-<50 mL/min), and severe (CrCL .gtoreq.15-<30
mL/min).
[0207] Scatter plots were used to examine the effect of continuous
variables and box plots were used for categorical variables. The
resulting graphs were screened using visual inspection, and the
most statistically relevant covariates were retained and evaluated
in the population PK model using an automatic stepwise forward
additive-backward elimination approach to identify individual
covariates that had a sufficient threshold effect based on the
specified criteria (P<0.01 for forward approach and P<0.001
for backward approach). Covariates were introduced in a
multiplicative order using a power model standardized by the median
for continuous covariates and a linear model with an exponentiated
factor relative to the reference for categorical covariates.
[0208] Final population PK model: evaluation and performance. The
final population-PK models for ceftolozane and tazobactam were
evaluated using standard diagnostics, goodness-of-fit criteria,
nonparametric bootstrap resampling, and visual predictive check
(VPC). Final model selection was based on goodness-of-fit criteria
evaluated using the log-likelihood difference between models,
pertinent graphical representations of plasma concentrations
(fitted, observed [individual dependent variable],
population-predicted [PRED], and individual-predicted [IPRED])
versus time plots with assumption of log-normal distribution of PK
parameters for BSV and BOV. Sensitivity of outliers was measured
using conditional weighted residuals (CWRES) versus time or time
after dose (for FOCE) plots. Shrinkage of individual random effects
(ETA) toward the population mean was computed to assess whether the
final model provided reliable estimates of individual PK
parameters: Shrinkage=1-(SD(ETA)/). SD(ETA) is the standard
deviation of the post hoc or empirical Bayesian estimates of ETA
and is the population model estimate of the SD of ETA. Smaller
shrinkage .ltoreq.0.2 indicates good individual estimates. A VPC
was performed to allow for comparisons of simulated and original
data. The plasma concentration-time profiles of ceftolozane and
tazobactam were simulated using 1000 replicates of the subject, and
the median 90% prediction intervals (PI) were computed and compared
with observed data. In addition, the robustness of the final
population PK model was confirmed using non-parametric bootstrap
resampling. The final model was fitted to a 1000 bootstrap dataset
to obtain the median value of each PK parameter, along with the
fixed-effect and random-effect parameters (inter-individual
variability and residual error). The nonparametric bootstrap values
(median) for each parameter were compared with the original
parameter estimates to examine bias and predictive error and were
evaluated using 95% confidence intervals (CIs).
Results
Data Sets
[0209] The population-PK model included evaluable data from 376
adults who received ceftolozane and 243 who also received
tazobactam, with 5048 observations for ceftolozane and 4249
observations for tazobactam. Demographic data stratified by
presence or absence of infection are summarized in FIG. 3.
Approximately, 39.9% (150/376) of subjects included in the PK model
had an infection (cUTI or cIAI) and 32.2% (121/376) were renally
impaired. Baseline CrCL was used to describe renal function since
serum creatinine was stable across the short treatment duration,
with a median value of the actual changes (increase or decrease) of
approximately 5% and a median value of the absolute changes of
<15%; all changes were judged as not clinically meaningful. The
age range of subjects was from 18 to 86 years.
Population Pharmacokinetic Model and Covariate Analysis of
Ceftolozane
[0210] A 2-compartmental structural model with a diagonal variance
(omega) of CL, Vc, peripheral volume of distribution (Vp), and
peripheral clearance (CL2) fixed to a value of 0 provided the best
data fit. The residual variability was found to be composite (both
proportional and additive). Covariate analysis showed that both CL
and Vc increased with body weight. A small negative trend between
age and CL was also observed but it was not clinically meaningful.
Both CL and Vc were significantly different for patients with an
infection compared with healthy volunteers, and ceftolozane CL
decreased as baseline CrCL decreased. Other covariates such as
race, sex, dose level, and drug-drug interaction did not
significantly affect CL or Vc of ceftolozane. The stepwise approach
to identify significant covariates showed that the greatest
improvement in the model included the effect of infection on both
CL (<0.001) and Vc (<0.001), body weight on Vc (<0.001),
and CrCL on CL (<0.001), with a significant difference between
the minimum objective function value for the tested and base models
[.DELTA.MOF2] of -329.81; P<0.001). The effects of renal
impairment and infection status on ceftolozane CL are presented in
a tornado plot (FIG. 4a). The plot shows that between-subject
variability (BSV 33.0%) had more impact on relative CL than the
effect of infection (cIAI or cUTI). Furthermore, severe renal
impairment and moderate renal impairment (based on CrCL categories
over a standardized range of 19.1-308.5 mL/min) resulted in lower
CL compared with normal and mild renal impairment.
[0211] The final model was further refined with infection status
divided into cUTI and cIAI. Overall, the refined final model for
ceftolozane was a 2-compartment model with linear elimination
including the effect of baseline CrCL on CL and body weight on Vc,
and the effect of cUTI and cIAI infection on both CL and Vc. The
population PK estimates, relative standard error (RSE), and BSV of
the model are shown in FIG. 5a. In the final refined model, the Vc
changed proportionally (linearly) with body weight in subjects
without cIAI. However, in cIAI patients, there was no significant
correlation between Vc and body weight given the large observed
variability. In addition, CL was similar in patients with cUTI and
cIAI (6.18 vs 6.23 L/h at CrCL=109 mL/min), both about 20% higher
than that in healthy subjects. Vc was about 30% different between
these 2 patient groups (13.8 L at 74 kg body weight for cUTI vs
18.2 L for cIAI). The inter-compartment clearance (CL2) was about 1
L/h while volume of distribution in the peripheral compartment was
about 3 L. The parameter estimates of the final model were reliable
with all standard error of measurement (SEM %) less than 50%, and
the residual variability (i.e., the sum of all variability that is
not explained by the final model) was low, 16.8% for proportional
error and 0.05 .mu.g/mL for additive error. For a fitted
ceftolozane concentration of 100 .mu.g/mL, the total residual error
would be 16.85 .mu.g/mL.
[0212] Diagnostic plots showed a good fit of the final model to
ceftolozane plasma concentrations (FIG. 6a). Individual observed
and PRED plasma concentrations were symmetrically distributed, and
CWRES versus PRED were homogenously distributed around 0 with 25 PK
samples from 20 subjects displaying CWRES >4, suggesting no bias
in predictions relating to low or high ceftolozane concentrations.
Outliers (CWRES >4) were not excluded from the analysis, as they
did not have a significant effect on PK parameters (difference
range: -0.2% to 6.7%) and the changes in BSV of CL and Vc were less
than 31%. VPC simulations were within the 90% PI of the predicted
median across all doses. Similarly, differences in PK parameters
and covariate effects between the final model and bootstrap runs
were <5%.
Population PK Model and Covariate Analysis of Tazobactam
[0213] The best-fit model for tazobactam was structurally similar
to that for ceftolozane, a 2-compartmental structural model with a
diagonal variance (BSV) for CL and Vc and a proportional model for
unexplained residual variability. Similar to ceftolozane, in the
covariate analysis differences in both CL and Vc were observed
between subjects with and without infection, and there was a strong
correlation between tazobactam CL and renal impairment category
(i.e., decrease in CL with decreasing baseline CrCL). The stepwise
approach to identify significant covariates showed that the
greatest improvement in the model included the effect of cIAI
infection on Vc (note there were no tazobactam data from cUTI
patients) and of CrCL on CL (.DELTA.MOF2: -92.84; P<0.001). The
.DELTA.MOF2 was -103.02 (P=0.001) when the effect of cIAI infection
was included in the model and -109.73 (P=0.01) when weight was
included on Vc. No trends were noted between other covariates
tested and tazobactam PK.
[0214] The final model was confirmed to be a 2-compartmental model
with linear elimination that included the effect of baseline CrCL
on CL showing a power function of 0.67 (i.e., [CrCL/115].sup.0.67)
and the effect of infection on Vc. In this model, the population
estimates (RSE %) derived for tazobactam were 18.0 L/h (3.39) for
CL, 14.2 L (4.45) for Vc in subjects without infection, 3.13 L/h
(4.59) for CL2 (inter-compartment clearance), and 4.29 L (2.61) for
Vp (FIG. 5b). The parameter estimates of the final model were
reliable with all SEM % less than 50%, and a proportional
unexplained error of 26.0% (1.64), although the BSV was higher
(50.2% for CL and 52.5% for Vc). The tornado plot shows that,
similar to ceftolozane, severe and moderate renal impairment
resulted in lower CL of tazobactam compared with normal and mild
renal impairment (FIG. 4b).
[0215] The model was robust showing a good fit to plasma
concentrations of tazobactam (FIG. 6b) and CWRES versus PRED were
homogenously distributed around 0 with 17 PK samples from 13
subjects displaying CWRES >4 and nonexclusion of outliers
(difference range: -2.8% to 7.7%). However, when outliers were
excluded the BSV of CL and Vc decreased by 42.5 and 32.5%,
respectively. VPC simulations were within 90% PIs of predicted
medians and differences in bootstrap resampling analysis were
<4% compared with the final model.
Conclusion
[0216] In summary, this analysis conducted by combining PK data
across a range of subjects provided a comprehensive, stable, and
interpretable model explaining the determinants of variability in
the disposition of ceftolozane/tazobactam. The final PK models
adequately described the plasma concentrations of ceftolozane and
tazobactam and form the basis for evaluation of the probability of
target attainment in a diverse population with varying demographics
and degrees of renal impairment. For both ceftolozane and
tazobactam that are primarily renally eliminated, clearance was
influenced by renal function. Other covariates tested, such as age,
body weight, sex, ethnicity and presence of infection, had no
clinically relevant effects on clearance. The model can be utilized
to further support optimal dosing scenarios to maximize efficacy
and safety of ceftolozane/tazobactam for treatment of serious
bacterial infections in subjects with varying degrees of renal
impairment. Monte Carlo simulations derived with the population
PK/PD model can also be utilized to further guide dosing
recommendations for ceftolozane/tazobactam in various populations,
for different pathogens of interest, and for other indications such
as nosocomial pneumonia infection.
Example 8 Single Dose Pharmacokinetics of Ceftolozane/Tazobactam
(as CXA-201) in Subjects with Severe Renal Impairment and End Stage
Renal Disease on Hemodialysis
[0217] Methods for reducing the concentration of ceftolozane in the
blood of a subject can include maintaining the subject on
hemodialysis for a period of 4 hours to remove about 66% of the
ceftolozane in the blood of the subject. This method is useful, for
example, in treating a patient after an overdose of ceftolozane,
and is based in part on the discovery that about 66% of ceftolozane
was removed from patients during dialysis (e.g., Example 8).
Study Design and Objectives
[0218] This was a Phase 1, multicenter, prospective, open-label
study of 750 mg ceftolozane/tazobactam (as CXA-201) administered IV
in male and female adult subjects with severe renal impairment
(estimated CL.sub.CR <30 mL/min) and subjects with end-stage
renal disease (ESRD) on hemodialysis (HD). The primary objective of
the study was to determine the PK profile of ceftolozane/tazobactam
in subjects with severe renal impairment and subjects with ESRD on
HD and to determine the effect of HD on the clearance of
ceftolozane/tazobactam.
[0219] Subjects with severe renal impairment received a single IV
1-hour infusion of 750 mg ceftolozane/tazobactam on Day 1. Subjects
with ESRD had a minimum of 3 months of HD prior to enrollment.
Subjects in this cohort received an IV dose of 750 mg
ceftolozane/tazobactam as a 1 hour infusion immediately after their
first HD session on Day 1 (post dialysis, approximately 72 hours
prior to the next HD session) and a second dose of
ceftolozane/tazobactam approximately 2 hours before their second HD
session on Day 4 of the study. Infusion of ceftolozane/tazobactam
was completed approximately 1 hour before the start of HD.
[0220] Subjects in both cohorts had urine (if not anuric) and
plasma samples collected for determination of levels of
ceftolozane, tazobactam and the M1 metabolite of tazobactam;
subjects in the ESRD on HD cohort also had dialysate fluid samples
collected for PK assessment. Plasma, urine, and dialysate levels of
ceftolozane, tazobactam, and its metabolite M1 collected over a
prespecified interval were determined by LC/MS/MS assay.
Results
[0221] A total of 12 subjects received 750 mg
ceftolozane/tazobactam: 6 subjects with severe renal impairment
received a single dose and 6 subjects with ESRD received a dose
prior to and following HD; all 12 subjects completed the study. A
total of 5 males and 7 females ranging in age from 40 to 76 years
were enrolled.
[0222] Details regarding the HD procedures for ESRD subjects,
including BUN collected before and after dialysis, are provided in
FIG. 14. All subjects underwent hemodialysis for 3 to 4 hours using
a high-flux membrane (either 1.4, 1.8, or 1.9 m.sup.2) on Days 1,
4, and 6 as scheduled. Average blood flow rate was 264 to 600
mL/min and average dialysis flow rate was either 600 or 800 mL/min
for all subjects with ESRD.
[0223] The PK parameters of ceftolozane, tazobactam, and the M1
metabolite of tazobactam were consistently higher in subjects with
severe renal impairment (Table 13) when compared with healthy
subjects or subjects with mild or moderate renal impairment from
previous studies.
TABLE-US-00018 TABLE 13 Plasma Pharmacokinetic Parameters for
Ceftolozane, Tazobactam, and Tazobactam M1 Metabolite in Subjects
with Severe Renal Impairment After a Single IV 1-hour Infusion of
750 mg Ceftolozane/Tazobactam Mean (CV %) Pharmacokinetic
Ceftolozane Tazobactam M1 Metabolite Parameter (N = 6) (n = 6) (n =
6) C.sub.max (.mu.g/mL) 49.9 (28) 15.2 (22) 2.2 (20) AUC.sub.last
(.mu.g h/mL) 511 (22) 50.3 (26) 53.7 (25) AUC.sub..infin. (.mu.g
h/mL) 537 (23) 52.4 (27) 60.3 (30) t.sub.1/2 (h) 11.1 (24) 2.6 (22)
12.0 (29) V.sub.ss (L) 13.8 (25) 16.5 (27) ND CL (L/h) 1.0 (20) 5.1
(29) ND AUC.sub..infin. = area under the plasma concentration-time
curve from time zero to infinity; AUC.sub.last = area under the
plasma concentration-time curve from time zero to the last
measurable concentration (plasma samples were obtained through 48
hours for subjects with severe renal impairment); CL = total body
clearance from plasma; C.sub.max = maximum (peak) plasma drug
concentration; CV = coefficient of variation; ND = not determined;
t.sub.1/2 = half-life; V.sub.ss = apparent volume of distribution
at steady state after intravenous administration
[0224] Due to relative increase in exposure, a 4-fold dose
reduction to 750 mg ceftolozane/tazobactam every 8 hours and 375 mg
ceftolozane/tazobactam every 8 hours is recommended in subjects
with moderate and severe renal impairment, respectively, compared
to 1.5 g ceftolozane/tazobactam dose in subjects with normal renal
function.
[0225] The PK parameters for ceftolozane, tazobactam, and the M1
metabolite of tazobactam in subjects with ESRD not being dialyzed
(dosed following HD) are summarized in Table 14. The plasma
concentrations of the M1 metabolite increased and did not appear to
decline over the 12 to 24 hour sampling interval. Therefore,
AUC.sub..infin. and t.sub.1/2 for the M1 metabolite could not be
calculated.
TABLE-US-00019 TABLE 14 Plasma Pharmacokinetics Parameters for
Ceftolozane, Tazobactam, and Tazobactam M1 Metabolite in Subjects
with ESRD on HD after the Day 1 Intravenous Infusion (During
Non-hemodialysis Phase) of 750 mg Ceftolozane/Tazobactam Mean (CV
%) Pharmacokinetic Ceftolozane Tazobactam M1 Metabolite Parameter
(N = 6) (n = 6) (n = 6) C.sub.max (.mu.g/mL) 44.5 (25) 21.2 (26)
10.0 (40) AUC.sub.last (.mu.g h/mL) 910 (35%) 103 (48) 367 (42)
AUC.sub..infin. (.mu.g h/mL) 1678 (44) 105 (47) ND t.sub.1/2 (h)
39.8 (33) 5.23 (42) ND V.sub.ss (L) 19.2 (36) 17.0 (35) ND CL (L/h)
0.4 (82) 3.0 (55) ND AUC.sub..infin. = area under the plasma
concentration-time curve from time zero to infinity; AUC.sub.last =
area under the plasma concentration-time curve from time zero to
the last measurable concentration (plasma samples were obtained
through 48 hours for subjects with ESRD on HD following Dose 1); CL
= total body clearance from plasma; C.sub.max = maximum (peak)
plasma drug concentration; CV = coefficient of variation; ND = not
determined; t.sub.1/2 = elimination half-life; V.sub.ss = apparent
volume of distribution at steady state after intravenous
administration
[0226] The PK parameters for ceftolozane, tazobactam, and the M1
metabolite of tazobactam in subjects dosed approximately 2 hours
prior to initiation of their 3 to 4 hour HD session are summarized
in Table 15. The concentrations of all 3 analytes increased
following the start of the infusion but declined rapidly at the
start of dialysis. The concentrations continued to decline during
HD and rebounded slightly at the end of HD followed by a slow
decline over the remainder of the sampling interval.
TABLE-US-00020 TABLE 15 Plasma Pharmacokinetics Parameters for
Ceftolozane, Tazobactam, and the M1 Metabolite of Tazobactam in
Subjects with ESRD on HD after the Second Intravenous Infusion of
750 mg Ceftolozane/Tazobactam on Day 4 (During HD) Mean (CV %)
Pharmacokinetic Ceftolozane Tazobactam M1 Metabolite Parameter (N =
6) (n = 6) (n = 6) C.sub.max (.mu.g/mL) 40.9 (35) |15.6 (37) 10.8
(46) t.sub.max (h).sup.(a) 1.0 (1.0, 1.0) 1.0 (1.0, 1.0) 1.5 (0.5,
24.0) AUC.sub.last (.mu.g h/mL) 304 (35) 38.4 (37) 176 (40)
t.sub.1/2 (h) 43.5 (19) 5.2 (44) ** AUC.sub.last = area under the
plasma concentration-time curve from time zero to the last
measurable concentration (plasma samples were obtained through 44
hours for subjects with ESRD on HD following Dose 2); C.sub.max =
maximum (peak) plasma drug concentration; CV = coefficient of
variation; ESRD = end-stage renal disease; HD = hemodialysis;
t.sub.1/2 = elimination half-life; t.sub.max = time to reach
maximum (peak) plasma concentration following drug administration
Median (minimum, maximum) presented. ** N = 1; one subject showed a
slow decline.
[0227] A separate analysis was conducted to determine the PK
parameters of ceftolozane, tazobactam, and the M1 metabolite of
tazobactam in subjects on HD following second dose of CXA-201 on
Study Day 4 from the start of the infusion to the end of dialysis.
This analysis was conducted in order to determine the PK parameters
from the start of infusion to the end of dialysis; results are
summarized in Table 16.
TABLE-US-00021 TABLE 16 Plasma Pharmacokinetics Parameters for
Ceftolozane, Tazobactam, and the M1 Metabolite of Tazobactam in
Subjects with ESRD on HD After the Second Intravenous Infusion of
750 mg Ceftolozane/Tazobactam on Day 4 (Start of Infusion to End of
Dialysis) Mean (CV %) Pharmacokinetic Ceftolozane Tazobactam M1
Metabolite Parameter (N = 6) (n = 6) (n = 6) C.sub.max (.mu.g/mL)
40.9 (35) 15.7 (37) 10.6 (49) t.sub.max (h).sup.(a) 1.0 (1.0, 1.0)
1.0 (1.0, 1.0) 1.5 (0.5, 1.5) AUC.sub.last (.mu.g h/mL) 87.5 (30)
28.8 (34) 23.8 (44) t.sub.1/2 (h) 1.25 (30) 0.98 (32) 1.54 (48)
AUC.sub.last = area under the plasma concentration-time curve for
approximately 6 hours from time of start of infusion to the end of
dialysis for subjects with ESRD on HD following Dose 2; C.sub.max =
maximum (peak) plasma drug concentration; CV = coefficient of
variation; ESRD = end-stage renal disease; HD = hemodialysis;
t.sub.1/2 = elimination half-life; t.sub.max = time to reach
maximum (peak) plasma concentration following drug administration.
Median (minimum, maximum) presented
[0228] Concentrations of ceftolozane, tazobactam, and the M1
metabolite declined rapidly following the start of HD. The median
exposure of ceftolozane/tazobactam (AUC.sub.48 h) during and after
dialysis is shown in Table 17. The data shows that a dosing
adjustment that replaces the fraction of ceftolozane/tazobactam,
removed due to dialysis, is recommended in subjects undergoing
intermittent dialysis.
TABLE-US-00022 TABLE 17 Exposure (AUC48h) of Ceftolozane,
Tazobactam, and the M1 Metabolite of Tazobactam in Subjects with
ESRD During and After Hemodialysis (HD) Median (Range) (.mu.g h/mL)
After HD During HD Ratio Percent Analyte (Day 1) (Day 3) (Day 3:1)
Removed Ceftolozane 903 298 (179-437) 0.34 (0.26-0.48) 66 (52-74)
(372-1233) Tazobactam 107 37.1 (19.9-57.8) 0.44 (0.26-0.53) 56
(47-74) (45.3-169) M1 389 182 (78-255) 0.49 (0.38-0.78) 51 (22-63)
Tazobactam (99.8-538) metabolite
[0229] Based on the results of this study, it is recommended that
ceftolozane/tazobactam be dosed following HD, and in the event of
an overdose, a standard 3 to 4 hour HD session with a high flux
membrane could lower plasma concentrations of ceftolozane,
tazobactam, and the M1 metabolite substantially. As a result, a
dosing adjustment that replaces the fraction of
ceftolozane/tazobactam removed due to dialysis is recommended in
subjects undergoing intermittent dialysis.
[0230] The recommended dose in subjects undergoing dialysis is a
single loading dose of 750 mg ceftolozane/tazobactam (500/250 mg)
administered every 8 hours by IV infusion followed after 8 hours by
a 150 mg every 8 hours maintenance dose of ceftolozane/tazobactam
(100/50 mg) for the remainder of the treatment period. On HD days,
the dose should be administered at the earliest possible time
following completion of dialysis. These doses are predicted to
provide total daily exposures of ceftolozane/tazobactam that are
comparable to exposures in subjects with normal renal function.
Pharmacokinetic Conclusions
[0231] The PK parameters of ceftolozane, tazobactam, and the M1
metabolite of tazobactam were influenced substantially in subjects
with severe renal impairment as well as in subjects with ESRD on HD
warranting dose adjustment.
Example 9A Ceftolozane/Tazobactam (as CXA-201) Dose Optimization in
Patients with End Stage Renal Disease (ESRD) Requiring Hemodialysis
(HD) Using Population Pharmacokinetics (pPK) and Monte Carlo
Simulations (MCS)
Objectives
[0232] This analysis was performed to characterize a) the PK
parameters for ceftolozane and tazobactam in subjects with end
stage renal disease (ESRD) on hemodialysis and b) assess
probability of target attainment (PTA) based on Monte Carlo
simulations and c) recommend optimal dosing regimens for clinical
use.
Data
[0233] Altogether per protocol, 156 plasma samples were collected
from 6 subjects with ESRD/hemodialysis. Out of the 156 plasma
samples, there were 141 valid ceftolozane plasma concentrations and
115 valid tazobactam plasma concentrations included for analysis.
The high level information about the study design is summarized in
FIG. 14A. The key demographics of the 6 subjects are summarized in
Table 18 below.
TABLE-US-00023 TABLE 18 Demographics of the Subjects with
ESRD/Hemodialysis Demographics Values (n = 6) Sex, n (%) Male 2
(33.3) Female 4 (66.7) Race, n(%) White 1 (16.7) Black or African
American 5 (83.3) Age (years) Mean (SD) 50.0 (11.08) Median
(minimum, maximum) 48.5 (40, 71) BMI (Kg/m.sup.2) Mean (SD) 28.9
(7.74) Median (minimum, maximum) 27.2 (21.4, 39.8)
[0234] Below the lower limit of quantification (BLLOQ) and missing
samples, if any, were not included for analysis, except the first
pre-dose sample. The individual plasma concentrations of
ceftolozane and tazobactam are listed in FIGS. 14B and C,
respectively. One ceftolozane concentration and 2 tazobactam
concentrations were excluded from analysis, as were done in the
clinical study report (CSR), because of their abnormal values.
[0235] Details regarding the HD procedures for ESRD subjects,
including BUN collected before and after dialysis, are provided in
FIG. 14D. All subjects underwent hemodialysis for 3 to 4 hours
using a high-flux membrane (either 1.4, 1.8, or 1.9 m.sup.2) on
Days 1, 4, and 6 as scheduled. Average blood flow rate was 264 to
600 mL/min and average dialysis flow rate was either 600 or 800
mL/min for all subjects with ESRD.
Methods
Software
[0236] Phoenix.TM. Non Linear Mixed Effects (NLME) version 1.2
(Pharsight Corporation, Certara USA, Inc., 9666 Olive Blvd., Suite
425, St. Louis, Mo. 63132 USA) with the extended least squares
first order conditional estimation (FOCE-ELS) was used for
population PK modeling and SAS.RTM. 9.3 (SAS Institute Inc., 100
SAS Campus Drive, Cary, N.C. 27513-2414, USA) with finite element
method (FEM) was used for Monte Carlo simulation. R (2.15.0) and
SAS.RTM. 9.3 were used for data management, statistical summaries
and table/figures generation.
[0237] The previously developed two-compartment disposition model,
as illustrated in FIG. 15, was used to fit the ceftolozane or
tazobactam plasma concentration-time data without hemodialysis and
to test the between subject variabilities (BSV) and the residual
variabilities. No other structural model was further tested unless
necessary. Ceftolozane or tazobactam plasma concentration-time data
with hemodialysis were then included and hemodialysis was tested as
a covariate effect on both clearance and volume of distribution for
the central compartment. The final model was selected based on the
stability of the model, reliability and interpretability of the
parameter estimates and the goodness-of-fit plots.
[0238] Where CL and Vc are clearance and volume of distribution for
the central compartment; CL2 is the inter-compartment clearance and
V2 is the volume of distribution for the peripheral
compartment.
Monte Carlo Simulations
[0239] The above obtained population PK model was then used to
simulate the ceftolozane/tazobactam concentration-time profiles in
patients with ESRD/hemodialysis. 5000 patients were simulated to
each of the following scenarios:
TABLE-US-00024 Loading Dose Maintenance Dose ( / ( / Scenario in
mg/mg) in mg/mg) Regimen 1 500/250 300/150 1-hr infusion, every 24
hours 2 -- 300/150 1-hr infusion, every 24 hours 3 600/300 300/150
1-hr infusion, every 24 hours 4 -- 100/50 1-hr infusion, every 8
hours 5 -- 300/150 4-hr infusion, every 24 hours 6 400/200 100/50
1-hr infusion, every 8 hours 7 500/250 100/50 1-hr infusion, every
8 hours TOL: Ceftolozane; TAZ: Tazobactam
[0240] Simulations with inflated between subject variabilities were
also conducted for the purpose of sensitivity analysis and risk
assessment. A finite element method with a time step of 0.001 hour
was used to simulate the plasma concentrations directly from the
mass balance differential equations as demonstrated in equations
1-3 below.
dA .times. .times. 1 dt = - K .times. .times. 12 .times. .times.
initial .times. .times. conditio .times. n: .times. .times. A
.times. .times. 1 = dose .times. .times. at .times. .times. t = 0 ;
( 1 ) dA .times. .times. 2 dt = K .times. .times. 1 .times. .times.
2 + K .times. .times. 32 .times. A .times. .times. 3 - ( K .times.
.times. 20 + K .times. .times. 23 ) .times. A .times. .times. 2
.times. .times. .times. initial .times. .times. conditio .times. n:
.times. .times. A .times. .times. 2 = 0 .times. .times. at .times.
.times. t = 0 ( 2 ) dA .times. .times. 3 dt = K .times. .times. 23
.times. A .times. .times. 2 - K .times. .times. 32 .times. A
.times. .times. 3 .times. .times. .times. .times. initial .times.
.times. .times. conditio .times. n: .times. .times. A .times.
.times. 3 = 0 .times. .times. at .times. .times. t = 0 ; ( 3 )
##EQU00001##
[0241] Where A1-A3 are the mass of ceftolozane or tazobactam at
time t in the infusion device, central compartment and peripheral
compartment, respectively; Kij represents the mass transport rate
constant from compartment i to compartment j, noting that
K12=Dose/infdur represents the infusion rate during infusion and 0
post the end of infusion with infdur standing for infusion
duration.
[0242] The solution to the above mass balance differential
equations using FEM at any given time t can be expressed as
below:
A1=A10-K12.times..DELTA.t (4)
A2=A20+[K12+K32.times.A30-(K20+K23).times.A20].times..DELTA.t
(5)
A3=A30+(K23.times.A20-K32.times.A30).times..DELTA.t (6)
[0243] Where .DELTA.t represents a small time step (e.g. 0.001
hour); A10, A20 and A30 are the masses in the infusion device,
central compartment and peripheral compartment at time t-.DELTA.t,
respectively. A1-A10, A2-A20 and A3-A30 represent the change of
mass during the small time step of .DELTA.t in the infusion device,
central compartment and peripheral compartment, respectively. Thus,
the plasma concentration Cp at any given time t can be calculated
as:
Cp = A .times. .times. 2 V .times. .times. 2 ( 7 ) ##EQU00002##
[0244] Where V2 is the volume of distribution for the central
compartment.
[0245] For ceftolozane, T>MIC and Probability of target
attainment (PTA) were based on a range of MIC from 0.03 to 128
.mu.g/mL.
[0246] For tazobactam, there is no MIC value since tazobactam
itself does not kill bacteria. However, it is believed that there
is somewhat threshold of tazobactam concentration that is needed to
inhibit beta-lactamase from hydrolyzing antibiotics (VanScoy B,
Mendes R E, et al. Pharmacological Basis of .beta.-Lactamase
Inhibitor Therapeutics: Tazobactam in Combination with Ceftolozane.
Antimicrobial Agents and Chemotherapy. 2013; 57(12):5924).
Therefore, similar to the minimum inhibitory concentration (MIC)
concept for antibiotic ceftolozane, a term of the minimum
efficacious concentration (MEC) is used for tazobactam,
representing the minimum concentration that is needed to
effectively inhibit resistance development of bacteria. Thus in
simulation, within each time step .DELTA.t, if Cp*fu is higher than
MIC (or MEC), the time step is accumulated into free time above MIC
(or MEC) for each patient against microorganisms with this MIC (or
MEC). Fu of 0.79 and 0.70 was used for the unbound fraction of
ceftolozane and tazobactam, respectively.
Results and Discussion
Data Characteristics
[0247] FIG. 16 and FIG. 17 illustrate the plasma concentration-time
profiles for ceftolozane and tazobactam, respectively, with or
without hemodialysis for 6 subjects (designated 1101-001-201 to
1101-001-0206). Both ceftolozane and tazobactam concentrations post
the end of infusion declined in a bi-exponential manner but only
ceftolozane had a long half-life in these subjects with
ESRD/hemodialysis as compared to those subjects with normal renal
function. Both ceftolozane and tazobactam concentrations were
rapidly reduced during hemodialysis, followed by a modest rebound
post the end of hemodialysis likely because of the redistribution
of the drug from peripheral compartment (tissue/organ) to the
central compartment (plasma). There was a large overall variability
in the concentration-time profiles across the six subjects as shown
in FIG. 16 and FIG. 17.
Ceftolozane Population PK Model in Subjects with ESRD
[0248] The population PK model for ceftolozane was developed via a
2-step process. First, the ceftolozane plasma concentrations
without hemodialysis (first dose) were modeled and best described
with a 2-compartment disposition model (FIG. 15) plus a
proportional residual error model. The between-subject variability
was reliably estimable on all four PK parameters CL, Vc, CL2 and
V2. When the ceftolozane plasma concentrations following the second
dose with hemodialysis were included, the above model, with the
addition of a dichotomous covariate and a between-subject
variability for the effect of hemodialysis, was the best to fit the
combined data. The final model was:
CL=0.340*exp{[4.09+N(0,0.696.sup.2)]*HD+N(0,0.522.sup.2)} (8)
Vc=6*exp{[1.54+N(0,0.400.sup.2)]*HD} (9)
CL2=19.2*exp{N(0,0.359.sup.2)} (10)
V2=11.8*exp{N(0,0.484.sup.2)} (11)
Cp_obs=Cp_ipred*[1+N(0,0.139.sup.2)] (12)
[0249] Where CL and Vc are the clearance and volume of distribution
for the central compartment; CL2 is inter-compartmental clearance
and V2 is volume of distribution for the peripheral compartment; HD
stands for hemodialysis (=1 during hemodialysis and =0 otherwise);
Cp_obs and Cp_ipred represent the observed and model-predicted
individual concentrations, respectively; and N(0, s.sup.2) stands
for a normal distribution centering at 0 with a standard error of s
(variance of s.sup.2). Exp( ) represents an exponential function on
the natural base. The detailed parameter estimates and their
standard errors are listed in Table 19.
TABLE-US-00025 TABLE 19 Parameter Estimates of the Population PK
Model for Ceftolozane Mean BSV % Parameters Estimate RSE % 95% CI
(RSE %) Vc, volume of 6 FIXED NA NA not estimable distribution for
central compartment V2, volume of 11.8 20.2 (7.1, 16.5) 48.4 (29.9)
distribution for peripheral compartment CL, terminal clearance
0.340 21.5 (0.2, 0.5) 52.2 (29.2) CL2, inter-compartmental 19.2
19.1 (12, 26.4) 35.9 (41.9) clearance Log-scale coefficient 1.54
11.8 (1.2, 1.9) 40.0 (34.7) of hemodialysis on Vc Log-scale
coefficient 4.09 7.1 (3.5, 4.7) 69.6 (29.8) of hemodialysis on CL
Residual variability (%) 13.9 6.5 NA Note: RSE stands for relative
standard error over mean; CI stands for confidence interval of the
mean estimate; BSV stands for between-subject-variability in
percentage; NA stands for not applicable.
[0250] When the ceftolozane concentrations with and without
hemodialysis were all combined together, the volume of distribution
for the central compartment (Vc) was not reliably estimable and was
therefore fixed at the value of 6, which was the estimate of the
model when only the concentrations following the first dose
(without hemodialysis) were included. Otherwise, the model was
stable, all converged to the same set of the final estimates with
different sets of initial estimates, and the parameter estimates
were all reliable and interpretable. The overall fitting was
reasonably good, as illustrated by the goodness-of-fit plots in
FIG. 18, the visual predictive check (VPC) in FIG. 19, and the
individual fitting plots in FIG. 20. As described by the model, the
terminal clearance is about 0.34 L/hr, with an apparent terminal
half-life of about 40 hours in subjects with ESRD as compared to
about 2 hours in subjects with normal renal function. Hemodialysis
removes ceftolozane at a clearance of about 20 L/hr. In addition,
hemodialysis also increased the apparent volume of distribution for
the central compartment from about 6 L to about 28 L. The
relatively large inter-compartment clearance of about 19 L/hr
suggests an almost instant equilibrium of ceftolozane concentration
between the peripheral compartment and the central compartment.
Tazobactam Population PK Model in Subjects with ESRD
[0251] Similar to ceftolozane, tazobactam plasma concentrations
without hemodialysis (first dose) were first modeled and well
described with a 2-compartment disposition model (FIG. 15) plus a
proportional residual error model. The between-subject variability
was reliably estimable on all four PK parameters CL, Vc, CL2 and
V2. When the tazobactam plasma concentrations following the second
dose were included, the model with hemodialysis evaluated as a
dichotomous covariate with a between-subject variability was the
best to fit all the combined data. The final model was:
CL=3.07*exp{[1.89+N(0,2.93.sup.2)]*HD+N(0,1.42.sup.2)} (13)
Ve=11.0*exp{0,434*HD+N(0,3.98.sup.2)} (14)
CL2=3.81 (15)
V2=6.55*exp{N(0,0.243.sup.2)} (16)
Cp_obs=Cp_inpred*[1+N(0,0.208.sup.2)] (17)
[0252] Where CL and Vc are the clearance and volume of distribution
for the central compartment; CL2 is inter-compartmental clearance
and V2 is volume of distribution for the peripheral compartment; HD
stands for hemodialysis (=1 during hemodialysis and =0 otherwise);
Cp_obs and Cp_ipred represent the observed and model-predicted
individual concentrations, respectively; N(0, s2) stands for a
normal distribution centering at 0 with a standard error of s
(variance of s2). Exp( ) stands for an exponential function on the
natural base.
[0253] The detailed parameter estimates and their standard errors
are listed in Table 20. The parameters were reliably estimated,
with SEM values less than 50%. Additional testing with different
sets of initial estimates confirmed that the model was stable--all
converged to the same set of final parameter estimates. The overall
quality of fitting was good as illustrated by the goodness-of-fit
plots in FIG. 21 and the VPC plot in FIG. 22. The individual
fitting was also reasonably good as illustrated in FIG. 23.
[0254] As described by the model, the terminal clearance was about
3 L/hr for tazobactam in subjects with ESRD, much larger than
ceftolozane due to its metabolic elimination path. The apparent
half-life was about 4 hours in subjects with ESRD as compared to
about 1 hour in subjects with normal renal function. Hemodialysis
increased the terminal clearance of tazobactam from about 3 L/hr to
about 20 L/hr and the apparent volume of distribution for the
central compartment from about 11 L to about 16 L. The estimated
BSV was very large in both clearance and volume of distribution,
partially reflecting the observed variability in this type of
subjects with ESRD and the fact of the small number of
subjects.
TABLE-US-00026 TABLE 20 Parameter Estimates of the Population PK
Model for Tazobactam Mean % Parameters Estimate RSE % 95% CI ,
volume of 11.0 16.4 (7.4, 14.5) 398 (34.3) distribution for central
compartment V2, Volume of 6.55 16.0 (4.5, 8.6) 24.3 (39.8)
distibution for peripheral compartment CL, terminal clearance 3.07
19.0 (1.9, 4.2) 142 (29.3) CL2, inter-compartmental 3.81 23.1 (2.1,
5.5) not estimable clearance Log-scale Coefficient 0.434 47.7 (0,
0.8) not estimable of hemodialysis on Log-scale Coefficient 1.89
11.7 (1.5, 2.3) 29 (31.4) of hemodialysis on CL Residual
variability (%) 20.8 7.7 not applicable Note: RSE stands for
relative standard error over mean; CI stands for confidence
interval of the mean estimate; stands for
between-subject-variability percentage.
Monte Carlo Simulations
[0255] Based on the above population PK model for ceftolozane and
tazobactam, a Monte Carlo simulation of 5000 subjects with end
stage renal disease was performed for each of the following
scenarios:
TABLE-US-00027 Loading Dose Maintenance Dose Scenario in mg/mg) in
mg/mg) Regimen 1 500/250 300/150 1-hr infusion, every 24 hours 2 --
300/150 1-hr infusion, every 24 hours 3 600/300 300/150 1-hr
infusion, every 24 hours 4 -- 100/50 1-hr infusion, every 8 hours 5
-- 300/150 4-hr infusion, every 24 hours 6 400/200 100/50 1-hr
infusion, every 8 hours 7 500/250 100/50 1-hr infusion, every 8
hours
[0256] The simulated treatment duration was set for 14 days. A
pre-dose 4-hour hemodialysis session was assumed on Monday,
Wednesday and Friday (or the last 4 hours of the previous dosing
day). Considering that only 6 subjects were used to estimate BSV
values, which might not be representative, a typical 50% BSV (i.e.,
a variance of 0.25) in log-scale was actually set in simulations
for all PK parameters except hemodialysis. For sensitivity analysis
and risk assessment, three additional situations were also
simulated for each of the above scenarios: [0257] a) The BSV values
as the model estimated; [0258] b) the BSV was inflated to 63% (or
0.40 for variance) in log-scale for the parameters with lower
model-estimated BSV, except for hemodialysis which was considered
to be machine related; [0259] c) the BSV was inflated to 63% (or
0.40 for variance) in log-scale if the model-estimate was lower and
deflated to 63% if the model-estimate was higher, except for
hemodialysis which was considered to be machine related.
[0260] The simulated results indicated that hemodialysis reduced
the residual accumulation, if any, from the previous dosing
regimens to a minimal level. In addition, for ceftolozane alone, of
which the terminal half-life was significantly extended in subjects
with ESRD as compared to the subjects with normal renal function,
all scenarios above were similar and covered the same level of MIC
of 8 .mu.g/mL with PTA >90%. The changes in BSV values as
described above did not change this conclusion although some
specific numbers might slightly change depending on the specific
situations. Obviously, the 1-hr once daily infusion is practically
the simplest and preferred dosing regimen for ceftolozane
alone.
[0261] However, the extension of the terminal half-life of
tazobactam in subjects with ESRD was not significant enough to
optimally justify a once-daily dosing regimen if its efficacy is
primarily driven by AUC and/or MEC, rather than Cmax.
[0262] In this case, a more frequent dosing regimen is preferred.
The simulated results suggested that at the same total daily dose,
a Q8h dosing regimen may potentially move the coverage of MEC
(analogy to MIC) up for 2 dilutions as compared to the Q24h dosing
regimen and a change in BSV may impact the coverage.
[0263] Therefore, with the considerations of maximizing ceftolozane
efficacy but limiting its daily AUC to be around/within 1100
.mu.ghr/mL that has previously been shown to be safe and tolerable
in humans (note, the maximum tolerable dose--MTD--has never been
reached), [0264] maximizing tazobactam efficacy in terms of MEC
coverage, [0265] maximizing the drug exposure on the first day to
maximally and rapidly kill bacterial and avoid/inhibit resistance
development, and [0266] the fixed ceftolozane/tazobactam (TOL/TAZ)
dose ratio of 2,
[0267] an optimal dosing regimen for clinical use in subjects with
ESRD/hemodialysis was suggested: a loading dose of 500 mg
ceftolozane/250 mg Tazobactam, followed by maintenance doses of 100
mg ceftolozane/50 mg Tazobactam, all for 1-hr infusion, three times
a day.
[0268] With this dosing regimen, the potential coverage of 8 mg/L
MIC for ceftolozane and about 1 mg/L MEC for tazobactam, will
result in a 90% target attainment on the first day. The simulated
results of this dosing regimen are described below.
[0269] For efficacy, FIG. 24 and FIG. 25 illustrate the simulated
total plasma concentration-time profiles for ceftolozane and
tazobactam, respectively. The simulated ceftolozane and tazobactam
plasma concentrations in subjects with ESRD were comparable to
those at the recommended clinical dose in patients with normal
renal function or other renal impairments
[0270] FIG. 26 and FIG. 27 illustrate their daily target
attainment. The achievable target attainments for the above
recommended dosing regimen in subjects with ESRD were also
comparable to those at the clinical dose in patients with normal
renal function. The detailed daily targeted attainment values for
ceftolozane and tazobactam are also tabulated in FIGS. 28 and 29,
respectively. For safety, Table 21 and Table 22 list the simulated
daily Cmax and AUC for ceftolozane and tazobactam, respectively.
The 95th percentile of the simulated daily AUC of ceftolozane for
the recommended dosing regimen was within the limit of 1100
.mu.g*hr/mL. Even in the worst case of the above tested BSV
situations, the maximum 95th percentile of the simulated daily AUC
values were within 15% of 1100 .mu.g*hr/mL and were limited on days
6-7 and 13-14 only--The 95th percentile of the simulated daily Cmax
and AUC for tazobactam for the recommended dosing regimen were
about 30 .mu.g/mL and 194 .mu.g*hr/mL, respectively, on day 1 and
down to about 8 .mu.g/mL and 100 .mu.g*hr/mL thereafter. These
values were in the safe range typically observed in clinical use
(Halstenson C E, Wong M O, Johnson C A, Zimmerman S W, Onorato J J,
Keane W F, et al. Pharmacokinetics of tazobactam M1 metabolite
after administration of Cmax 1994; 34(12):1208-17). In the worst
case where the model-estimated abnormally large BSV values were
used for CL and Vc while the BSV values for CL2 and V2 were
inflated to 50% in log-scale, the potential 95th percentile of
daily Cmax and AUC for tazobactam were 74 .mu.g/mL and 418
.mu.g*hr/mL, respectively, on day 1 and down to about 23 .mu.g/mL
and 340 .mu.g*hr/mL thereafter. These values were in the range that
other recommended clinical dosing regimens would have reached for
tazobactam e.g. in Zosyn.RTM. (see Halstenson (1994) cited
above).
[0271] In summary, the dosing regimen of 500/250
(ceftolozane/Tazobactam in mg/mg) loading dose, followed by a
100/50 maintenance dose for 1-hr infusion, three times a day is
optimal and therefore recommended for clinical use.
TABLE-US-00028 TABLE 21 Simulated Median (5th, 95th percentile)
Daily Cmax and AUC of Total Ceftolozane for the Dosing Regimen: a
Loading Dose of 500 mg ceftolozane/250 mg Tazobactam + Maintenance
Doses of 100 mg ceftolozane/50 mg Tazobactam, All for 1-hr Infusion
Every 8 Hours. (log- scale 50% BSV, N = 5000) Daily C.sub.max Daily
AUC Day Median (5.sup.th, 95.sup.th percentile) Median (5.sup.th,
95.sup.th percentile) 1 38.4 (23.2, 63) 610 (362.1, 1008) 2 33.5
(20.6, 54) 583.3 (334.1, 969) 3 21.7 (12.6, 52) 339.4 (180.4, 754)
4 28 (16.7, 47) 455.3 (253, 841) 5 21 (12.3, 54) 323.9 (173.5, 784)
6 27.7 (16.5, 48) 520.7 (290.4, 981) 7 32.1 (18.5, 55) 550.1
(294.8, 1010) 8 21.5 (12.5, 62) 337.2 (177.8, 871) 9 28.2 (16.7,
50) 456.2 (251.2, 916) 10 21 (12.3, 59) 324 (173.7, 834) 11 27.8
(16.5, 50) 448.2 (248.3, 892) 12 20.9 (12.3, 58) 322.2 (173, 827)
13 27.7 (16.5, 49) 520.6 (290.3, 1016) 14 32.1 (18.5, 56) 550.3
(294.8, 1045)
TABLE-US-00029 TABLE 22 Simulated Median (5th, 95th percentile)
Daily Cmax and AUC of Total Tazobactam for the Dosing Regimen: a
Loading Dose of 500 mg ceftolozane/250 mg Tazobactam + Maintenance
Doses of 100 mg ceftolozane/50 mg Tazobactam, All for 1-hr Infusion
Every 8 Hours. (log-scale 50% BSV, N = 5000) Daily Cmax Daily AUC
Day Median (5.sup.th, 95.sup.th percentile) Median (5.sup.th,
95.sup.th percentile) 1 17.1 (8.6, 30) 103.1 (48.7, 194) 2 4.7
(2.6, 8) 47 (20.5, 115) 3 4.3 (2.5, 8) 44.2 (20.7, 93) 4 4.4 (2.5,
8) 45 (20.3, 100) 5 4.3 (2.5, 7) 44.1 (20.7, 91) 6 4.4 (2.5, 8)
48.5 (21.5, 108) 7 4.4 (2.5, 8) 45.2 (20.3, 103) 8 4.3 (2.5, 7)
44.1 (20.7, 92) 9 4.4 (2.5, 8) 44.9 (20.3, 99) 10 4.3 (2.5, 7) 44.1
(20.7, 91) 11 4.4 (2.5, 8) 44.9 (20.3, 99) 12 4.3 (2.5, 7) 44.1
(20.7, 99) 11 4.4 (2.5, 8) 48.5 (21.5, 108) 14 4.4 (2.5, 8) 45.2
(20.3, 103)
Conclusions
[0272] Ceftolozane/tazobactam plasma concentrations following
ceftolozane/Tazobactam infusion in subjects with ESRD and
hemodialysis can be best described with a 2-compartment disposition
model plus a covariate effect of hemodialysis on both clearance and
volume of distribution of the central compartment. [0273] The
residual accumulation, if any, from previous doses prior to each
hemodialysis is manageable. [0274] Ceftolozane terminal half-life
is significantly extended such that a daily or Q 8 hr dosing
regimen in subjects with ESRD are equally adequate in achieving PTA
of >90% for an MIC of up to 8 .mu.g/mL. [0275] Tazobactam
terminal half-life is modestly extended but not long enough to
justify changing the Q 8 hr dosing regimen to a daily dosing
regimen,
[0276] With consideration of maximizing tazobactam efficacy and
limiting ceftolozane daily AUC around or within 1100 .mu.g/mL, an
optimal dosing regimen is recommended for clinical use in subjects
with ESRD: a single loading dose of 500 mg ceftolozane/250 mg
tazobactam via 1-hr IV infusion, followed in 8 hr by a maintenance
dose of 100 mg ceftolozane/50 mg tazobactam via 1-hr infusion every
8 hours. A maintenance dose is suggested to be given at the
earliest possible time post the end of each hemodialysis
session.
Example 9B: Ceftolozane/Tazobactam Dose Optimization in Patients
with End-Stage Renal Disease Requiring Hemodialysis Using
Population Pharmacokinetics and Monte Carlo Simulations
Abstract
Background
[0277] Ceftolozane/tazobactam (TOL/TAZ) is being developed for
treatment of complicated urinary tract infection and
intra-abdominal infection. The objective of this study was to
characterize the population pharmacokinetics (pPK) of TOL/TAZ,
determine the probability of target attainment (PTA) of various
dosing regimens, and identify the optimal clinical dose in subjects
with end-stage renal disease (ESRD) on hemodialysis (HD).
Methods:
[0278] Ceftolozane/tazobactam plasma concentrations from 6 subjects
with ESRD following a single dose without HD and a second dose with
HD were used to develop a pPK model (Phoenix NLME). Monte Carlo
stimulation was performed (SAS 9.3) to predict individual
Ceftolozane/tazobactam concentrations in 5000 subjects to assess
the PTA for different dosing regimens and test a range of free-drug
time above minimum inhibitory concentration (MIC) (fT>MIC)
targets, including 24.8% for bacteriostasis, 32.2% for bactericidal
activity (1-log kill) as well as higher thresholds for bactericidal
effects up to 60% fT>MIC. Monte Carlo simulations used
ceftolozane MIC determined with 4 mg/L tazobactam.
Results:
[0279] A 2-compartment disposition model plus a covariate effect of
HD best described the observed Ceftolozane/tazobactam plasma
concentrations. The key parameter estimates for the final pPK model
were: for ceftolozane, terminal clearance (CL) and central volume
of distribution (V.sub.c) of 0.34 L/h and 6 L, respectively, with
HD increasing CL and V.sub.c by 60- and 4.7-fold, respectively; for
tazobactam, CL and V.sub.c of 3.07 L/h and 11 L, respectively, with
HD increasing CL and V.sub.c by 6.6- and 1.5-fold, respectively.
PTA exceeded 90% for an MIC up to 8 mg/L for ceftolozane across all
the tested scenarios. Out of all the tested scenarios, the 500
mg/250 mg Ceftolozane/tazobactam single loading dose followed by
100 mg/50 mg every 8 hours maintenance dose via 1-hour infusion
achieved a >99% PTA against all targets up to an MIC of 8 mg/L
on day 1 (FIG. 30A) and >97% PTA on all other days without HD.
The PTA for bactericidal activity on post HD days was 89% (FIG.
30B).
Conclusion
[0280] Plasma concentrations following Ceftolozane/tazobactam
infusion in subjects with ESRD on HD can be best described with a
2-compartment disposition model plus a covariate effect of HD on
both CL and V.sub.c. In patients with ESRD on HD, a single loading
dose of 500 mg/250 mg Ceftolozane/tazobactam infused over 1 hour,
followed by 100 mg/50 mg every 8 hours infused over 1 hour,
preferably at the earliest possible time following completion of
each dialysis, achieved a high PTA and was identified as the
optimal dose.
Introduction
[0281] Ceftolozane/tazobactam is a novel antibacterial with
activity against Pseudomonas aeruginosa, including drug-resistant
strains, and other common Gram-negative pathogens, including most
extended-spectrum .beta.-lactamase (ESBL)-producing
Enterobacteriaceae. Ceftolozane/tazobactam is primarily eliminated
by the kidneys, and its clearance would be expected to be reduced
in those with impaired renal function. Data from the 2 renal
impairment studies suggested that a decrease in the dose, frequency
of administration, or both is necessary for those patients with
moderate or severe renal impairment or end-stage renal disease
(ESRD).
[0282] The objectives of this analysis were to characterize the
pharmacokinetic (PK) parameters for ceftolozane and tazobactam in
subjects with ESRD on hemodialysis, determine the probability of
target attainment (PTA) of various dosing regimens and identify the
optimal dose in patients with ESRD on hemodialysis.
Methods
[0283] Phoenix.TM. NLME version 1.2 (Pharsight Corporation, Certara
USA, Inc.; St. Louis, Mo.) with the extended least squares first
order conditional estimation was used for population PK modeling
and SAS.RTM. 9.3 (SAS Institute Inc., Cary, N.C.) was used for the
Monte Carlo simulation.
Population PK Modeling
[0284] Ceftolozane/tazobactam plasma concentrations collected from
6 patients with ESRD following a single dose without hemodialysis
and a second dose with hemodialysis were used to develop a
population PK model (Phoenix.TM. Non Linear Mixed Effects
[NLME]).
[0285] A 2-compartment disposition model was used to fit the
ceftolozane or tazobactam plasma concentration-time data without
hemodialysis and to test the between-subject variability and
residual variability. Ceftolozane or tazobactam plasma
concentration-time data with hemodialysis were then included and
hemodialysis was tested as a covariate effect on both clearance and
volume of distribution for the central compartment.
[0286] The final model was selected based on the stability of the
model, reliability and interpretability of the parameter estimates,
and the goodness-of-fit plots.
Monte Carlo Simulations
[0287] The population PK model was used to simulate the
ceftolozane/tazobactam concentration-time profiles in patients with
ESRD/hemodialysis.
[0288] Monte Carlo simulations were performed to predict individual
ceftolozane/tazobactam concentrations in 5000 patients to assess
the PTA for each of 7 different dosing regimens (Table 23),
narrowed down stepwise from many potential scenarios that might
meet the criteria on free-drug time above minimum inhibitory
concentration (fT>MIC), maximum concentration (C.sub.max), and
daily area under the curve (AUC) that assure both efficacy and
safety. A range of fT>MIC targets were tested, including 24.8%
for bacteriostasis, 32.2% for bactericidal activity (1-log kill),
which were the targets for ceftolozane/tazobactam efficacy as
previously determined in a murine-thigh infection model,.sup.4 as
well as higher thresholds for bactericidal effects up to 60%
fT>MIC.
TABLE-US-00030 TABLE 23 Monte Carlo Simulation Dosing Regimens
Loading Dose Maintenance Dose MIC <8 with >25% MEC <0.5
with >40% Daily (TOL/TAZ in (TOL/TAZ in fT > MIC at 90% fT
> MEC at 90% AUC >1100 mg/L Scenario mg/mg) mg/mg) Regimen
PTA for TOL? PTA for TAZ? hr for TOL? Outcome.sup.a 1 -- 100/50 1-h
infusion, Y N Y F every 8 h 2 -- 300/150 1-h infusion, Y Y Y F
every 24 h 3 -- 300/150 4-h infusion, Y Y N F every 24 h 4 400/200
100/50 1-h infusion, Y N Y F every 8 h 5 600/300 300/150 1-h
infusion, N Y Y F every 24 h 6 500/250 300/150 1-h infusion, N Y Y
F every 24 h 7 500/250 100/50 1-h infusion, N N N S every 8 h
.sup.aA simulation is a success if the response to the 3 questions
is no. AUC = area under the curve; F = failure; fT > MIC =
free-drug time above minimum inhibitory concentration; MEC =
minimum efficacious concentration; N = No; PTA = probability of
target attainment; S = success; TAZ = tazobactam; TOL =
ceftolozane; Y = Yes.
[0289] Monte Carlo simulations used ceftolozane MIC determined with
4 mg/L tazobactam.
[0290] The final dosing regimen was selected based on: [0291]
Maximizing ceftolozane efficacy but limiting its daily AUC to be
within 1100 mgh/L, which has previously been shown to be safe and
tolerable in humans (note, the maximum tolerable dose has never
been reached), [0292] Maximizing tazobactam efficacy in terms of
minimum efficacious concentration (MEC) coverage, [0293] Maximizing
the drug exposure on the first day to maximally and rapidly kill
bacterial and avoid/inhibit resistance development, and [0294] A
fixed ceftolozane/tazobactam dose ratio of 2:1.
Results
Data Characteristics
[0295] 156 plasma samples were collected from 6 patients with ESRD
on hemodialysis; 66.7% were female, 83.3% were black or African
American, the mean (SD) age was 50.0 (11.1) and the mean (SD) body
mass index was 28.9 kg/m2 (7.7).
[0296] Both ceftolozane and tazobactam concentrations declined in a
bi-exponential manner (FIG. 29) following the end of infusion, but
only ceftolozane had a long half-life compared with patients with
normal renal function.3
[0297] Both ceftolozane and tazobactam concentrations were rapidly
reduced during hemodialysis, followed by a modest rebound following
the end of hemodialysis likely due to the redistribution of the
drug from the peripheral compartment to the central compartment
(FIG. 29). There was a large variability in the concentration-time
profiles across the 6 patients.
Population PK Model in Patients with ESRD
[0298] A 2-compartment disposition model plus a covariate effect of
hemodialysis best described the observed ceftolozane/tazobactam
plasma concentrations.
[0299] The key parameter estimates for the final population PK
model are set forth in Table 24.
TABLE-US-00031 TABLE 24 Population PK Parameter Estimates for
Ceftolozane and Tazobactam Ceftolozane Tazobactam Mean BSV % Mean
BSV % Parameters Estimate RSE % 95% CI (RSE %) Estimate RSE % 95%
CI (RSE %) V.sub.c, volume of distribution 6 FIXED NA NA not 11.0
16.4 (7.4-14.5) 398 (34.3) for central compartment estimable
V.sub.2, Volume of distribution 11.8 20.2 (7.1-16.5) 48.4 (29.9)
6.55 16.0 (4.5-8.6) 24.3 (39.8) for peripheral compartment CL,
terminal clearance 0.34 21.5 (0.2-0.5) 52.2 (29.2) 3.1 19.0
(1.9-4.2) 142 (29.3) CL.sub.2, inter-compartmental 19.2 19.1 .sup.
(12-26.4) 35.9 (41.9) 3.8 23.1 (2.1-5.5) Not clearance estimable
Log-scale coefficient of 1.5 11.8 (1.2-1.9) 40.0 (34.7) 0.43 47.7
.sup. (0-0.8) Not hemodialysis on V.sub.c estimable Log-scale
coefficient of 4.1 7.1 (3.5-4.7) 69.6 (29.8) 1.9 11.7 (1.5-2.3) 29
(31.4) hemodialysis on CL Residual variability (%) 13.9 6.5 NA 20.8
7.7 NA BSV = between-subject variability in percentage; CI =
confidence interval of the mean estimate; NA = not applicable; RSE
= relative standard error over mean.
[0300] For ceftolozane, terminal clearance (CL) and central volume
of distribution (V.sub.c) were 0.34 L/h and 6 L, respectively, with
hemodialysis increasing CL and V.sub.c by 60- and 4.7-fold,
respectively. For tazobactam, CL and V.sub.c were 3.07 L/h and 11
L, respectively, with HD increasing CL and V.sub.c by 6.6- and
1.5-fold, respectively.
Monte Carlo Simulations
[0301] PTA exceeded 90% for an MIC up to 8 mg/L for ceftolozane
across all the tested scenarios (data not shown).
[0302] Out of all the tested scenarios, the optimal dosing regimen
of ceftolozane/tazobactam for clinical use in patients with
ESRD/hemodialysis is a single loading dose of 500 mg/250 mg
ceftolozane/tazobactam, followed by a maintenance dose of 100 mg/50
mg every 8 hours, all as 1-hour infusions (Table 23).
[0303] For ceftolozane, this dosing regimen achieved a >99% PTA
against all targets up to an MIC of 8 mg/L on day 1 (FIG. 7A) and
>97% PTA on all other days without HD. The PTA for bactericidal
activity on post HD days was 89% (FIG. 7B).
[0304] For tazobactam, the optimal dosing regimen achieved a
>94% PTA against a target up to an MEC of 1 mg/L on day 1 (FIG.
30C) and >94% PTA on day 3 (FIG. 30D) and all other days without
hemodialysis.
[0305] Table 25 lists the simulated daily C.sub.max and AUC for
ceftolozane and tazobactam.
[0306] The 95th percentile of the simulated daily AUC of
ceftolozane for the recommended dosing regimen was within the limit
of 1100 mgh/L, the highest daily exposure achieved in clinical
trials that was proved to be safe. For comparison, the median daily
steady-state AUC values in subjects with normal renal is observed
to be 690 mgh/L (Wooley M, et al. Antimicrob Agents Chemother.
2014; 58: 2249-2255).
[0307] The 95th percentile of the simulated daily AUC for
tazobactam for the recommended dosing regimen was approximately 194
mgh/L, respectively on day 1 and down to approximately 100 mgh/L
thereafter. These values were in the safe range typically observed
in clinical studies with the median steady-state AUC value in
normal renal subjects estimated to be 89.4 mgh/L, respectively.
TABLE-US-00032 TABLE 25 Simulated Median (5th, 95th percentile)
Daily Cmax and AUC of Total Ceftolozane and Tazobactam Ceftolozane
Tazobactam Daily C.sub.max Daily AUC Daily C.sub.max Daily AUC
Median (5th, Median (5th, Median Median 95th 95th (5th, 95th (5th,
95th Day Percentile) Percentile) Percentile) Percentile) 1 38.4
(23.2, 63) 610 (362.1, 1008) 17.1 103.1 (8.6, 30) (48.7, 194) 2
33.5 (20.6, 54) 583.3 (334.1, 969) 4.7 (2.6, 8) 47 (20.5, 115) 3
21.7 (12.6, 52) 339.4 (180.4, 754) 4.3 (2.5, 8) 44.2 (20.7, 93) 4
28 (16.7, 47) 455.3 (253, 841) 4.4 (2.5, 8) 45 (20.3, 100) 5 21
(12.3, 54) 323.9 (173.5, 784) 4.3 (2.5, 7) 44.1 (20.7, 91) 6 27.7
(16.5, 48) 520.7 (290.4, 981) 4.4 (2.5, 8) 48.5 (21.5, 108) 7 32.1
(18.5, 55) 550.1 (294.8, 1010) 4.4 (2.5, 8) 45.2 (20.3, 103) 8 21.5
(12.5, 62) 337.2 (177.8, 871) 4.3 (2.5, 7) 44.1 (20.7, 92) 9 28.2
(16.7, 50) 456.2 (251.2, 916) 4.4 (2.5, 8) 44.9 (20.3, 99) 10 21
(12.3, 59) 324 (173.7, 834) 4.3 (2.5, 7) 44.1 (20.7, 91) 11 27.8
(16.5, 50) 448.2 (248.3, 892) 4.4 (2.5, 8) 44.9 (20.3, 99) 12 20.9
(12.3, 58) 322.2 (173, 827) 4.3 (2.5, 7) 44.1 (20.7, 91) 13 27.7
(16.5, 49) 520.6 (290.3, 1016) 4.4 (2.5, 8) 48.5 (21.5, 108) 14
32.1 (18.5, 56) 550.3 (294.8, 1045) 4.4 (2.5, 8) 45.2 (20.3, 103)
Dosing regimen: a loading dose of 500 mg/250 mg
ceftolozane/tazobactam + maintenance doses of 100 mg/50 mg, all for
1-h infusion every 8 hours (log-scale 50% BSV, N = 5000) AUC = area
under the curve; C.sub.max = maximum concentration.
Conclusions
[0308] Plasma concentrations following ceftolozane/tazobactam
infusion in patients with ESRD on hemodialysis can be best
described with a 2-compartment disposition model plus a covariate
effect of hemodialysis on both CL and V.sub.c.
[0309] In patients with ESRD on hemodialysis, a single loading dose
of 500 mg/250 mg ceftolozane/tazobactam infused over 1 hour,
followed by 100 mg/50 mg every 8 hours infused over 1 hour,
achieved a high PTA and was identified as the optimal dose.
Example 10 Pharmacodynamic Target Attainment Analyses Supporting
the Selection of In Vitro Susceptibility Test Interpretive Criteria
for Ceftolozane/Tazobactam (as CXA-201) Against Pseudomonas
aeruginosa
[0310] Modeling is used to show that the dosages recommend for the
different renal types is appropriate to hit the PK/PD targets of %
T>MIC
[0311] The human phase 1 and 2 PK data was used in a Monte Carlo
model to predict the curves at the dosing regimens and the
probability that the drug levels would be high enough at the
corresponding MIC values.
Monte Carlo Simulation
[0312] Using SAS 9.2 [SAS 9.2 for Windows [computer program]. Cary,
N.C.: SAS Institute Inc. 2010] Version Monte Carlo simulation was
conducted to generate 5,000 patients, with 1,000 in each of five
renal function categories. These categories (and corresponding
creatinine clearance (CLcr) ranges) were as follows: [0313] High
normal renal function (150< to .ltoreq.200 mL/min); [0314]
Normal renal function (90< to .ltoreq.150 mL/min); [0315] Mild
renal impairment (50< to .ltoreq.90 mL/min); [0316] Moderate
renal impairment (29.ltoreq. to .ltoreq.50 mL/min); and [0317]
Severe renal impairment (15.ltoreq. to <29 mL/min). [0318] Using
the fixed and random effects parameter estimates and
variance-covariance matrix from a previously-developed population
PK model for ceftolozane, plasma concentration-time profiles for
ceftolozane were generated for simulated patients in each renal
function category following selected CXA-201 dosing regimens.
[0319] CXA-201 dosing regimens administered over 1 hr every 8 hrs.
(q8h) by renal function category included 1000 mg and 2000 mg
ceftolozane adjusted for renal function categories as follows:
[0320] 1000 mg ceftolozane regimens: [0321] 1000/500 mg CXA-201 in
patients with high normal and normal renal function and patients
with mild renal impairment; [0322] 500/250 mg CXA-201 in patients
with moderate renal impairment; and [0323] 250/125 mg CXA-201 in
patients with severe renal impairment. [0324] 2000 mg ceftolozane
regimens: [0325] 2000/1000 mg CXA-201 in patients with high normal
and normal renal function and patients with mild renal impairment;
[0326] 1000/500 mg CXA-201 in patients with moderate renal
impairment; and [0327] 500/250 mg CXA-201 in patients with severe
renal impairment. [0328] As the activity of ceftolozane is not
enhanced significantly by Tazobactam due to lack of inhibition of
AmpC beta-lactamase [SAS 9.2 for Windows [computer program]. Cary,
N.C.: SAS Institute Inc. 2010], only ceftolozane exposures were
considered in these analyses.
PK-PK Target Attainment Analyses
[0328] [0329] Using non-clinical PK-PD targets, PK-PD TA by MIC was
assessed for simulated patients in each renal function category in
the context of MIC distributions for CXA-201 against P. aeruginosa
based on surveillance data from the United States (US) and the
European Union (EU). [0330] Non-clinical PK-PD targets were based
on the results from a neutropenic murine-thigh infection model in
which P. aeruginosa was evaluated JMI Laboratories. Surveillance of
ceftolozane/tazobactam antimicrobial activity when tested against
Gram-negative organisms and streptococci isolated in the USA
(2012). Final Report. February 2013; Craig W A, Andes DR.
Antimicrob Agents Chemother. 2013; 57:1577-82] [0331] The
percentage of the dosing interval that concentrations are above the
MIC (% T>MIC) was the PK-PD driver most associated with efficacy
for ceftolozane. [0332] For the PK-PD analyses carried out,
free-drug (f) % T>MIC targets of 24.8 and 32.2, which were
associated with net bacterial stasis and a 1-log.sub.10 colony
forming units (CFU) reduction from baseline, respectively, and f %
T>MIC targets of 40, 50, and 60 were assessed. [0333] The
percentage of simulated patients that attained these targets during
the dosing interval at steady-state for MIC values ranging from
0.03 to .gtoreq.32.2 mg/L was determined for each ceftolozane
dosing regimen evaluated within each renal function category.
[0334] For patients severe renal impairment administered CXA-201
250/125 mg q8h a PK-PD MIC cut-off value of 8 mg/L was identified
(which is similar to the cutoff predicted for the 1.5 g dose for
normal renal function).
[0335] The PK-PD MIC cutoff values for CXA-201 1000 and 2000 mg q8h
dosing regimens against P. aeruginosa by renal function category is
shown in Table 26.
TABLE-US-00033 TABLE 26 PK-PD MIC Cutoff Values for CXA-201 Dosing
Regimens Against P. aeruginosa by Renal Function Category %
simulated patients achieving free-drug Renal function CXA-201
dosing MIC fT > MIC targets category.sup.A regimen (mg).sup.B
(mg/L).sup.C 24.8/.gtoreq.32.2.sup.D High normal 1000/500 4
99.5/96.1 2000/1000 8 99.5/96.1 Normal 1000/500 8 99.1/94.7
2000/1000 16 99.1/94.7 Mild 1000/500 8 100/99.8 2000/1000 16
100/99.8 Moderate 500/250 8 99.9/99.5 1000/500 16 99.9/99.5 Severe
250/125 8 98.4/96.1 500/250 16 98.4/96.1 .sup.ARenal function
categories were defined as follows: High normal function = CLcr
(mL/min) <150-.ltoreq.200; Normal renal function = CLcr (mL/min)
<90-.ltoreq.150; Mild renal impairment = CLcr (mL/min)
<50-.ltoreq.90; Moderate renal impairment = CLcr (mL/min)
<29-.ltoreq.50; Severe renal impairment = CLcr (mL/min)
<15-.ltoreq.29. .sup.BCXA-201 administration via 1 h intravenous
infusion Q8h. .sup.CRepresents the highest MIC associated with
.gtoreq.90% PK-PDTA.
Example 11: Impact of Renal Function on the Pharmacokinetics and
Safety of Ceftolozane/Tazobactam
[0336] The pharmacokinetics (PK) of ceftolozane/tazobactam in
patients with normal renal function are linear across a wide range
of doses (up to 3,000 mg/1,500 mg as a single dose). Terminal
elimination half-lives (t.sub.1/2) are approximately 2.5 h for
ceftolozane and 1 h for tazobactam. Both compounds exhibit low
protein binding (approximately 20% for ceftolozane and 30% for
tazobactam) and are primarily excreted in the urine; ceftolozane as
unchanged parent drug suggesting minimal metabolism, and tazobactam
with 80% as the unchanged parent drug and the remaining as inactive
M1 metabolite. In the present studies, the PK and safety of
ceftolozane/tazobactam were investigated in subjects with varying
degrees of renal function, including subjects with end-stage renal
disease (ESRD) on hemodialysis (HD).
Materials and Methods
Study Populations
[0337] Male and female subjects, aged 18 to 79 years, with varying
degrees of renal function were enrolled in two, prospective,
open-label, phase I studies of intravenous ceftolozane/tazobactam.
A total of 36 subjects were enrolled into cohorts based on degree
of renal function: normal (n=11), mild impairment (n=6), moderate
impairment (n=7), severe impairment (n=6), and ESRD on HD (n=6). To
ensure subjects with ESRD were receiving effective HD, a target
adequacy of HD calculated from the pre- and post-blood urea
nitrogen ratios (Kt/V) of at least 1.2 for a minimum of 3 months
prior to enrollment was required. Renal impairment groups were
classified according to the 2010 U.S. Food and Drug Administration
draft guidance using creatinine clearance (CrCl) estimated by the
Cockcroft-Gault formula (normal impairment, >90 ml/min; mild
impairment, 60 to 89 ml/min; moderate impairment, 30 to 59 ml/min;
and severe impairment, 15 to 29 ml/min, ESRD <15 ml/min).
Dosing/Design
[0338] All cohorts received ceftolozane/tazobactam as an
intravenous infusion over 1 h. The normal, mild, and moderate renal
impairment cohorts received a single dose of ceftolozane/tazobactam
1,000 mg/500 mg; the severe renal impairment cohort received a
single dose of ceftolozane/tazobactam 500 mg/250 mg; the ESRD
cohort received a dose of ceftolozane/tazobactam 500 mg/250 mg
initiated at the end of HD on day 1 and another dose initiated 2 h
before HD on day 4. Subjects with ESRD underwent HD for 3 to 4 h
using a high-flux membrane as scheduled; average dialysis flow rate
was 600 to 800 ml/min. Revaclear hemodialyzers (Gambro, Stockholm,
Sweden) were used in 5 subjects (ultrafiltration coefficient 50 to
60 ml/h/mmHg, high flux membrane of 1.4 to 1.8 m.sup.2) and a CT
190G hemodialyzer (Baxter Healthcare, McGaw Park, Ill.) was used in
1 subject (ultrafiltration coefficient 36 ml/h/mmHg, high flux
membrane of 1.9 m.sup.2). The average blood flow rate was 400 to
600 ml/min with the exception of one subject with rates between 264
and 400 ml/min.
Pharmacokinetic Evaluations
[0339] Plasma concentrations of ceftolozane and tazobactam were
measured prior to, during, and following administration of
ceftolozane/tazobactam. Blood samples were collected 30 min prior
to administration, at the end of administration and at 5, 15, and
30 min and 1, 2, 3, 5, 7, 9, 11, 15, 25, and 35 h after completion
of ceftolozane/tazobactam administration in the normal, mild, and
moderate renal impairment cohorts. Severe renal impairment and ESRD
cohorts off HD had samples taken 30 min prior to administration and
at 0.5, 1, 1.5, 2, 3, 6, 9, 12, 24, 36, and 48 h after the start of
administration. On the day of and following HD, the subjects with
ESRD had samples taken 30 min prior to administration and at 0.5,
1, 1.5, 2, 3, 4, 5, 6, 9, 12, 24, 36, and 44 h after the start of
the administration. The entire dialysate was collected at each of
the following intervals: 0 to 1, 1 to 2, 2 to 3, and 3 h to the end
of dialysis. Urine for PK analysis was obtained in the normal,
mild, and moderate cohorts at 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12
to 24, and 24 to 36 h after the start of ceftolozane/tazobactam
administration. In the ESRD and severe renal impairment cohorts,
urine was collected during the confinement period pre-dose, 0 to 24
h, and 24 to 48 h after the start of the administration, unless the
subject was anuric. A validated LC/MS/MS method was utilized to
analyze all plasma, urine, and dialysate samples for ceftolozane
and tazobactam (MicroConstants Inc., San Diego, Calif.) (4). The
lower limit of quantification (LLOQ) in plasma was 0.25 .mu.g/ml
for ceftolozane and 0.1 .mu.g/ml for tazobactam. The assay was
linear between 0.25 and 150 .mu.g/ml for ceftolozane and between
0.1 and 50 .mu.g/ml for tazobactam. The precision of the assay for
ceftolozane and tazobactam ranged between 3.13 and 7.97% while the
accuracy was .+-.1 and .+-.6.25%, respectively. The LLOQ in
dialysate for both ceftolozane and tazobactam was 1 ng/ml and the
assay was linear between 1 and 500 ng/ml. The precision of the
assay in dialysate samples for ceftolozane and tazobactam ranged
between 1.28 and 9.18% while the accuracy for ceftolozane and
tazobactam was .+-.8.3 and .+-.9.67%, respectively. The LLOQ for
ceftolozane and tazobactam in urine was 5 and 10 .mu.g/ml,
respectively, and the assay was linear between 5 and 5,000 .mu.g/ml
for ceftolozane and between 10 and 10,000 .mu.g/ml for tazobactam.
The precision of the assay for ceftolozane and tazobactam ranged
between 3.71 and 9.06% while the accuracy was .+-.9.20 and 7.33%,
respectively.
[0340] Pre-dose values below the LLOQ values were set to zero and
all missing values below the LLOQ obtained after the first
quantifiable concentration were designated as missing and not
included in the analysis. The maximum plasma concentration
(C.sub.max) and plasma concentration when the last quantifiable
concentration was observed relative to the end of infusion
(C.sub.last) were taken directly from concentration-time data.
Terminal elimination t.sub.1/2 was calculated as
0.693/.lamda..sub.z where .lamda..sub.z is the terminal elimination
rate constant, estimated by regression of the terminal log-linear
phase of the plasma concentration versus time curve. Area under the
plasma concentration time curve (AUC) from time zero to the last
measurable concentration (AUC.sub.0-t) was calculated using the
linear trapezoidal rule. The AUC extrapolated to infinity
(AUC.sub.0-.infin.) was estimated using the formula
AUC.sub.0-last+(C.sub.last/.lamda..sub.z) using the linear
trapezoidal rule. Total body clearance from plasma (CL) was
calculated as dose/AUC.sub.0-.infin.. Volume of distribution at
steady-state (V.sub.ss) was calculated as mean residence time*CL.
Renal clearance (CL.sub.r) in subjects that provided urine samples
was calculated from the equation CL.sub.r=A.sub.e/AUC.sub.0-.infin.
where A.sub.e is the cumulative amount of drug recovered in the
urine during the sampling period. Dialysis clearance was calculated
as the amount of ceftolozane or tazobactam recovered in dialysate
divided by AUC from the time of the second dose to the end of HD
(AUC.sub.(t0-t1)). The rate of decrease in plasma concentration
(RDHD) was calculated from the difference between the concentration
at the end of dialysis (C.sub.2) and the concentration at the
beginning of HD (C.sub.1). The percent reduction was calculated
using the equation RDHD=100*(C.sub.1-C.sub.2)/C.sub.1. Extraction
ratio was calculated as 100*(C.sub.A-C.sub.V)/C.sub.A where C.sub.A
and C.sub.V are pre- and post-dialyzer paired drug concentrations
at the arterial and venous sites. Total effective removal was
calculated with individual AUC.sub.0-.infin. values as
(AUC.sub.off-HD-AUC.sub.on-HD) divided by AUC.sub.off-HD (6).
Dialysis clearance (CL.sub.D) was calculated as amount of drug in
dialysate divided by AUC.sub.(t0-t1).
[0341] The PK parameters were calculated by non-compartmental
analysis using Phoenix WinNonlin version 6.1 (Pharsight
Corporation, Mountain View, Calif.).
Safety Monitoring
[0342] Safety was assessed by monitoring for adverse events (AEs)
from the first dose of drug through the last study evaluation, and
by review of vital signs, physical examinations, 12-lead
electrocardiograms, and clinical laboratory evaluations.
Results
Demographics and Disposition
[0343] A total of 36 subjects received ceftolozane/tazobactam. No
subjects withdrew consent or discontinued due to an AE, and all
subjects were included in the PK and safety analyses. The
demographic characteristics of the subjects are presented in FIG.
8. The majority were white, except in the ESRD cohort in whom five
of the six subjects were black or African American. Subjects ranged
in age from 40 to 79 years with a median age of 62 years.
Pharmacokinetic Summary
Normal Renal Function and Mild, Moderate, and Severe Renal
Impairment
[0344] Compared with subjects with normal renal function, the
concentration-time profiles of ceftolozane/tazobactam were
increasingly altered in subjects with increasingly impaired renal
function (FIGS. 11A and 11B). Pharmacokinetic parameters are
summarized in FIGS. 9 and 10 for ceftolozane and tazobactam,
respectively. Ceftolozane and tazobactam plasma clearance by CrCl
are provided in FIGS. 12A and 12B, respectively. Exposure
(AUC.sub.0-.infin. and C.sub.max) was similar in subjects with
normal renal function and mild renal impairment following a single
ceftolozane/tazobactam 1,000 mg/500 mg dose as was t.sub.1/2. In
subjects with moderate renal impairment, decreases in clearance led
to increased ceftolozane and tazobactam exposure compared with
subjects with normal renal function with median AUC.sub.0-.infin.
and C.sub.max increased for ceftolozane (2.5- and 1.2-fold,
respectively) and tazobactam (2.2- and 1.6-fold, respectively). In
subjects with severe renal impairment, the median AUC.sub.0-.infin.
and C.sub.max increased 4.4- and 1.3-fold for ceftolozane and 3.8-
and 1.9-fold for tazobactam, respectively, compared with the
dose-normalized exposure in the normal renal function group.
End-Stage Renal Disease on Hemodialysis
[0345] Median concentration-time profiles for ceftolozane and
tazobactam in subjects with ESRD post-HD and on HD are shown in
FIGS. 13A and 13B, respectively. The PK parameters of ceftolozane
and tazobactam differed substantially in subjects with ESRD
compared with the other renal impairment groups. Pharmacokinetic
parameters are summarized in FIGS. 9 and 10 for ceftolozane and
tazobactam, respectively. The median elimination t.sub.1/2 of
ceftolozane and tazobactam in subjects with ESRD during non-HD was
prolonged and the median C. in plasma was 1.2- and 2.4-fold higher
compared with subjects with normal renal function when dose
normalized. The t.sub.1/2 during the HD period for ceftolozane and
tazobactam were 1.13 and 0.91 h, respectively. The extraction
ratios at 1 h and 2 h after the start of HD and at end of HD for
ceftolozane and tazobactam were 42, 48, and 47% and 48, 54, and
55%, respectively. The average extraction ratio during HD was 46%
(.+-.16) for ceftolozane and 53% (.+-.22) for tazobactam.
Ceftolozane and tazobactam concentrations declined rapidly
following the start of HD with approximately 66 and 56% reductions
in overall exposure to ceftolozane and tazobactam, respectively,
based on the AUC.sub.0-.infin. on and off HD. The median RDHD for
ceftolozane and tazobactam was 92 and 95%, respectively, indicating
significant removal by HD; however, in the period following HD,
plasma concentrations rebounded and peaked at approximately 17 and
6% of the original C. of ceftolozane and tazobactam, respectively.
The median CL.sub.D for ceftolozane and tazobactam was 5.75 and
4.39 liter/h, respectively.
Safety
[0346] Overall, seven of the 36 subjects experienced a total of 12
AEs. The most common AE reported was headache in three subjects.
All events reported were mild in severity with the exception of one
event of moderate headache in a subject with normal renal function.
Two subjects with normal renal function and one subject with mild
renal impairment reported the AE of headache. Diarrhea,
infusion-site hemorrhage, and injection-site hemorrhage were
reported in one subject each in the mild impairment group.
Flatulence, glossodynia, myalgia, and vulvovaginal pain were
reported in one subject each in the ESRD on HD group. No AEs were
reported in the moderate or severe renal impairment groups. One
serious AE of thrombosis of an arteriovenous fistula was reported
in a subject with ESRD on HD 7 days after the last dose of the
study drug. No subjects withdrew due to AEs. Review of clinical
laboratory values, physical examination, and vital signs showed no
meaningful changes from baseline.
[0347] In summary, the exposure to ceftolozane/tazobactam in
subjects with mild renal impairment was increased relative to that
in normal controls, but the increase was small and not clinically
meaningful, suggesting that no dose adjustment is necessary in this
population. However, data from these phase I studies suggest that a
decrease in dose or frequency of administration, or both, is
necessary in those with moderate or severe renal impairment, or
with ESRD.
Example 12: Ceftolozane/Tazobactam Dosing
[0348] Out of the 7 tested dosing regimens listed below (Table 27),
all failed except the last one (scenario 7) which was recommended
for clinical use. The failure was defined if not meeting:
[0349] 1). PTA.gtoreq.90% and fT>MIC .gtoreq.32.2% (1-log kill)
on day 1 and 2 or >=24.8% on any of the other later days for CXA
at MIC=8 mg/L; and
[0350] 2). Daily AUC is about or less than 1100 mg/L*hr every day;
and
[0351] 3). PTA.gtoreq.90% at about 50% fT>MEC for MEC=0.5 mg/L
for Taz.
TABLE-US-00034 TABLE 27 Tested dosing regimens Loading Dose
Maintenance Dose (TOL/TAZ (TOL/TAZ Scenario in mg/mg) in mg/mg)
Regimen 1 500/250 300/150 1-hr infusion, every 24 hours 2 --
300/150 1-hr infusion, every 24 hours 3 600/300 300/150 1-hr
infusion, every 24 hours 4 -- 100/50 1-hr infusion, every 8 hours 5
-- 300/150 4-hr infusion, every 24 hours 6 400/200 100/50 1-hr
infusion, every 8 hours 7 500/250 100/50 1-hr infusion, every 8
hours
Example 13: Cardiac Safety Study: Single Dose Pharmacokinetics and
Effects on the QT/QTc Interval of Ceftolozane/Tazobactam
Study Design and Objectives:
[0352] This TQT study was a single-center, prospective, randomized,
double-blind, double-dummy, placebo and active controlled, 4-way
crossover study that evaluated a single therapeutic 1.5 g and a
single supratherapeutic 4.5 g dose of ceftolozane/tazobactam
compared with placebo. Moxifloxacin 400 mg, given orally, was used
as a positive control. All subjects received study drug on 4 dosing
days (Day 1, Day 5, Day 9, and Day 13) in a crossover fashion with
a 3-day wash-out period between doses. Healthy men and women were
randomized on a 1:1:1:1 basis to 1 of 4 dosing sequences.
[0353] The primary objectives of the study were to evaluate the
effect of a single IV supratherapeutic dose of
ceftolozane/tazobactam on ventricular repolarization as measured by
QTc interval in healthy subjects compared to baseline-adjusted,
time-matched placebo and to evaluate the change from the
period-specific predose baseline of QT/QTc interval corrected by
QTcI (individual QT correction subject-specific formula) across all
dose groups. Pharmacokinetics of ceftolozane/tazobactam was a
secondary objective of this study.
[0354] Electrocardiograms were recorded (triplicate measurements)
over 24 hours on Day 1, Day 5, Day 9, and Day 13 using a 12-lead
Holter monitor. Blood samples for determination of ceftolozane,
tazobactam, and the M1 metabolite of tazobactam levels were
obtained at prespecified time intervals prior to and following each
electrocardiogram (ECG) reading on dosing days. Plasma levels of
ceftolozane, tazobactam, and its metabolite M1 were determined by
LC/MS/MS assay.
Results:
[0355] A total of 52 healthy volunteers were randomized into the
study, including 13 in each dosing sequence. Two subjects withdrew
prematurely, including 1 subject who withdrew after receiving both
the therapeutic and supratherapeutic doses of
ceftolozane/tazobactam and 1 who withdrew after receiving only
moxifloxacin. The latter subject was not included in the PK
analyses. The 51 subjects in the PK analyses included 28 males and
23 females who ranged in age from 18 to 45 years.
[0356] A single dose of ceftolozane/tazobactam 1.5 g or 4.5 g did
not increase QTc intervals. The largest mean difference from
placebo for changes from predose in QTcI (.DELTA..DELTA.QTcI) was
4.16 msec observed 1 hour following dosing with
ceftolozane/tazobactam 4.5 g, and the largest one-sided 95% upper
confidence bound was 6.25 msec. The 95% lower confidence bounds on
the differences from baseline for QTcI between moxifloxacin and
placebo was above 5 ms. These data indicate the study's sensitivity
to demonstrate a sufficiently small QTc change.
[0357] Following dosing with both therapeutic and supratherapeutic
doses of ceftolozane/tazobactam, mean ceftolozane C.sub.max,
AUC.sub.last and AUC.sub..infin. appeared to increase in a
dose-proportional manner (Table 28). Ceftolozane plasma t.sub.1/2,
CL, and V.sub.ss were comparable for therapeutic and
supratherapeutic doses. Further, results of the ANOVA confirmed
dose proportionality between the therapeutic and supratherapeutic
doses as the ratio of least square (LS) means and 90% CIs of
ceftolozane PK parameters were all within the 80% to 125% range.
The ceftolozane plasma concentration-time profile is shown in FIG.
31.
[0358] Similar to ceftolozane, mean C.sub.max, AUC.sub.last and
AUC.sub..infin. of tazobactam and its M1 metabolite appeared to
increase in a dose-proportional manner when the tazobactam dose was
increased from 500 mg to 1.5 g. Tazobactam mean plasma t.sub.1/2,
CL, and V.sub.ss were comparable for therapeutic and
supratherapeutic doses (Table 29). The tazobactam plasma
concentration-time profile is shown in FIG. 32. Median t.sub.max of
the M1 metabolite of tazobactam was 3.7 hours, which was longer
than the median t.sub.max for ceftolozane or tazobactam. Mean
plasma t.sub.1/2 of metabolite M1 was 3.6 hours for the
supratherapeutic dose and was similar to that observed for the
therapeutic dose (3.2 hours). Results of the ANOVA confirmed dose
proportionality between the therapeutic and supratherapeutic doses
as the ratio of LS means and 90% CIs of both tazobactam and
metabolite M1 AUC and C.sub.max were all within the 80% to 125%
range (Table 28).
TABLE-US-00035 TABLE 28 Ceftolozane Plasma Pharmacokinetic
Parameters after Administration of Therapeutic (1.5 g) and
Supratherapeutic (4.5 g) Intravenous 1-hour Infusions of
Ceftolozane/Tazobactam Mean (CV %) Ceftolozane/Tazobactam
Ceftolozane/Tazobactam Therapeutic Dose Supratherapeutic Dose
Ceftolozane 1000/500 mg 3000/1500 mg PK Parameter (n = 51) (n = 51)
C.sub.max (.mu.g/mL) 66.5 (19) 199 (19) t.sub.max (h)a) 0.667
(0.667, 1.17) 0.667 (0.667, 1.18) AUC.sub.last (.mu.g h/mL) 184
(18) 560 (18) AUC.sub..infin. (.mu.g h/mL) 186 (18) 562 (17)
t.sub.1/2 (h) 2.29 (15) 2.72 (21) V.sub.ss (L) 13.5 (21) 13.7 (20)
CL (L/h) 5.57 (18) 5.50 (17) AUC.sub..infin. = area under the
plasma concentration-time curve from time zero to infinity;
AUC.sub.last = area under the plasma concentration-time curve from
time zero to the last measureable concentration (plasma samples
were obtained through 22.5 hours); CL = total body clearance from
plasma; C.sub.max = maximum (peak) plasma drug concentration; CV =
coefficient of variation; PK = pharmacokinetic; t.sub.1/2 =
elimination half-life; tmax = time to reach maximum (peak) plasma
concentration following drug administration; V.sub.ss = apparent
volume of distribution at steady state after intravenous
administration a)Median (minimum, maximum) presented
TABLE-US-00036 TABLE 29 Tazobactam Plasma Pharmacokinetic
Parameters after Administration of Therapeutic (1.5 g) and
Supratherapeutic (4.5 g) Intravenous 1-hour Infusions of
Ceftolozane/Tazobactam Mean (CV %) Ceftolozane/Tazobactam
Ceftolozane/Tazobactam Tazobactam 1000/500 mg 3000/1500 mg PK
Parameter (n = 51) (n = 51) C.sub.max (.mu.g/mL) 18.6 (23) 51.2
(21) t.sub.max (h)a) 0.667 (0.667-1.17) 0.667 (0.667, 1.17)
AUC.sub.last (.mu.g h/mL) 23.5 (24) 73.1 (19) AUC.sub..infin.
(.mu.g h/mL) 23.8 (24) 73.4 (19) t.sub.1/2 (h) 0.870 (18) 1.05 (17)
V.sub.ss (L) 18.2 (25) 19.3 (22) CL (L/h) 22.1 (21) 21.2 (19)
AUC.sub..infin. = area under the plasma concentration-time curve
from time zero to infinity; AUC.sub.last = area under the area
under the plasma concentration-time curve from time zero to the
last measurable concentration (plasma samples were obtained through
22.5 hours); CL = total body clearance from plasma; C.sub.max =
maximum (peak) plasma drug concentration; CV = coefficient of
variation; PK = pharmacokinetic; t.sub.1/2 = elimination half-life;
t.sub.max = time to reach maximum (peak) plasma concentration
following drug administration; V.sub.ss = apparent volume of
distribution at steady state after intravenous administration
a)Median (minimum, maximum) presented
[0359] As the sample size in this study was large, with an aim to
enroll an equal number of males and females, it provided the
opportunity to evaluate the effect of gender on PK. Results of the
ANOVA indicated that ceftolozane AUC was 22% higher in females
compared to males while tazobactam AUC was 19% higher. This
increase in AUC was not considered clinically meaningful since
ceftolozane/tazobactam doses up to 3 g administered every 8 hours
were safe and well tolerated. Further, as shown in FIG. 33, which
presents body weight adjusted CL values for 28 males and 23
females, no clinically relevant gender differences were observed in
the PK of ceftolozane/tazobactam at the proposed therapeutic dose
of 1.5 g ceftolozane/tazobactam. The results for M1 metabolite of
tazobactam as well as at the supratherapeutic dose also were in
agreement with this observation.
Pharmacokinetic Conclusions:
[0360] The C.sub.max and AUC were dose proportional across
therapeutic and supratherapeutic doses of ceftolozane/tazobactam,
with the 4.5 g supratherapeutic dose providing a large margin of
safety regarding ECG changes.
[0361] Gender did not influence the PK of ceftolozane to a
clinically relevant extent.
Example 14: Pharmacokinetic-Pharmacodynamic Target Attainment
Analyses Supporting the Selection of In Vitro Susceptibility Test
Interpretive Criteria for Ceftolozane/Tazobactam Against
Enterobacteriaceae
Abstract
[0362] Objectives: The objective of these analyses was to provide
support for the selection of susceptibility breakpoints for
ceftolozane/tazobactam (TOL/TAZ) against Enterobacteriaceae,
including those isolates producing extended-spectrum beta-lactamase
(ESBL).
[0363] Methods: Using the fixed and random effects parameter
estimates and variance-covariance matrix from previously-developed
population PK models for TOL and TAZ, plasma concentration-time
profiles were generated for simulated patients in 5 renal function
categories (1000 patients/category). Using non-clinical PK-PD
targets, PK-PD target attainment by MIC value was assessed for
simulated patients in each renal function category in the context
of MIC distributions for TOL/TAZ against the Enterobacteriaceae,
including the ESBL-producing isolates, collected during the course
of the clinical trial program. For TOL, free-drug % T>MIC
targets of 24.8 and 32.2, which were associated with net bacterial
stasis and 1-log 10 CFU reduction from baseline in a neutropenic
murine-thigh infection model, were assessed. For TAZ, a free-drug %
T>threshold (1/2 of the TOL/TAZ MIC) of 65.9, which was
identified in an in vitro infection model, was assessed. For the
ESBL-negative isolates, the percentage of simulated patients that
attained the above-described TOL targets was calculated. For
ESBL-positive isolates, a multi-step, sequential algorithm was used
to assess PK-PD target attainment that required sufficient TOL and
TAZ exposures.
[0364] Results: As expected, the percentage of simulated patients
achieving free-drug PK-PD targets for TOL (% T>MIC) and TAZ (%
T>threshold) increased as the MIC value or the magnitude of the
target decreased. Table 32 shows the highest MIC value for which
target attainment was .gtoreq.80% by renal function category and
dose regimen.
[0365] Conclusions: These data will be used as susceptibility
breakpoint decision support.
Introduction
[0366] The U.S. FDA and consensus organizations, such as the
Clinical Laboratory Standards Institute (CLSI) and European
Committee on Antimicrobial Susceptibility Testing (EUCAST)
establish in vitro susceptibility test interpretive criteria (i.e.,
susceptibility breakpoints).
[0367] Clinical microbiology laboratories provide physicians
qualitative test results using susceptibility breakpoints (i.e.,
susceptible, intermediate, or resistant) as a guide to effective
antimicrobial chemotherapy.
[0368] Ceftolozane/tazobactam (TOL/TAZ), which has potent in vitro
activity against a wide variety of Gram-negative pathogens,
including multi-drug resistant Pseudomonas aeruginosa, is being
developed as a first-line intravenous (IV) therapy for the
treatment of serious Gram-negative bacterial infections, including
complicated urinary tract infections and intra-abdominal
infections.
[0369] Pharmacokinetic-pharmacodynamic (PK-PD) target attainment
analyses described herein were carried out to provide support for
the selection of in vitro susceptibility test interpretive criteria
for TOL/TAZ against Enterobacteriaceae.
Objectives
[0370] The objectives of these analyses were to conduct PK-PD
target attainment analyses to provide support for the
following:
[0371] Recommendations for in vitro susceptibility test
interpretive criteria for TOL/TAZ against Enterobacteriaceae
(beta-lactamase producers and non-producers); and
[0372] Selected TOL/TAZ dosing regimens by renal function
groups.
Methods
Monte Carlo Simulation
[0373] Using SAS Version 9.2, Monte Carlo simulation was conducted
to generate 5,000 patients, with 1,000 in each of five renal
function categories. These categories (and corresponding creatinine
clearance (CLcr) ranges) are shown in Table 30.
[0374] Using the fixed and random effects parameter estimates and
variance-covariance matrix from previously-developed population PK
models for TOL and TAZ (Table 31), plasma concentration-time
profiles were generated for simulated patients in each renal
function group following administration of TOL/TAZ 1000 and 2000 mg
dosing regimens over 1 h every 8 h (q8h) adjusted for renal
function (Table 30).
TABLE-US-00037 TABLE 30 TOL/TAZ Dosing Regimens by Renal Function
Group TOL/TAZ dosing regimens (mg) Renal function group 1000/500
TOL/TAZ 2000/1000 TOL/TAZ High normal renal function 1000/500
2000/1000 (150< to .ltoreq.200 mL/min); Normal renal function
1000/500 2000/1000 (90< to .ltoreq.150 mL/min); Mild renal
impairment 1000/500 2000/1000 (50< to .ltoreq.90 mL/min);
Moderate renal impairment 500/250 1000/500 (29.ltoreq. to
.ltoreq.50 mL/min); Severe renal impairment 250/125 500/250
(15.ltoreq. to <29 mL/min)
TABLE-US-00038 TABLE 31 Parameter Estimates and Associated
Precision from the Population PK Model for TOL and TAZ TOL.sup.e
TAZ.sup.f PK parameter Interindividual variability PK parameter
Interindividual variability Relative Relative Relative Relative
Population standard Estimate standard Population standard Estimate
standard Parameter estimate error (%) (%) error (%) estimate error
(%) (%) error (%) CL (L/hr).sup.a 5.14 2.30 34.3 3.91 18.0 3.39
50.2 4.98 Exponent of the relationship 0.75 6.01 NA NA 0.67 11.1 NA
NA between CLcr and CL Proportional shift in CL for 1.26 16.5 NA NA
NA NA NA NA infected patients V.sub.c (L).sup.b 11.8 2.4 34.0 4.80
14.2 4.45 52.5 6.14 Exponent of the relationship 0.76 13.9 NA NA NA
NA NA NA between weight and CL Proportional shift in V.sub.c for
infected patients 1.37 13.0 NA NA 1.47 21.9 NA NA CL.sub.d
(L/hr).sup.c 0.884 3.79 0 (fixed) NA 3.13 4.59 0 (fixed) NA V.sub.c
(L).sup.d 2.88 2.15 0 (fixed) NA 4.29 2.61 0 (fixed) NA
Proportional residual error (%) 19.3 1.14 NA NA 26.0 1.64 NA NA
.sup.aCL is the central clearance (L/hr). .sup.bV.sub.c is the
central volume of distribution (L). CL.sub.d is the
intercompartmental clearance (L/hr). .sup.cV.sub.c is the
peripheral volume of distribution (L). .sup.eCL (infected patients)
= 5.14 (CLcr/109).sup.0.75 1.26. V.sub.c (infected patients) = 11.8
(weight/74).sup.0.75 1.37. .sup.fCL = (8.0 (CLcr/115).sup.0.67
V.sub.c (infected patients) = 14.2 1.47. NA = not applicable.
PK-PD Target Attainment Analyses
[0375] Using non-clinical PK-PD targets, PK-PD target attainment by
MIC was assessed for simulated patients in each renal function
group in the context of MIC distributions for TOL and/or TOL/TAZ
against the Enterobacteriaceae, including the ESBL-producing
isolates, which was comprised of data from 4 studies involving
patients with either complicated urinary tract infections or
complicated intra-abdominal infections.
[0376] For TOL, the percentage of the dosing interval that
concentrations were above the MIC (% T>MIC) was the PK-PD
measure most associated with efficacy.
[0377] Results of the PK-PD analyses based on data from a
neutropenic murine-thigh model demonstrated that TOL free-drug %
T>MIC targets of 24.8 and 32.2 were associated with net
bacterial stasis and a 1-log 10 CFU reduction from baseline,
respectively.
[0378] In addition to assessing PK-PD target attainment for these
targets, free-drug % T>MIC targets of 40, 50, and 60 were also
assessed.
[0379] For TAZ, the PK-PD measure associated with efficacy was the
percentage of the dosing interval that TAZ concentrations were
above a threshold concentration (% T>threshold).
[0380] Data from a PK-PD in vitro infection model demonstrated that
the optimal value for the TAZ threshold concentration was one-half
the TOL/TAZ MIC value.
[0381] For the assessment of PK-PD target attainment, the TAZ
target, free-drug % T>threshold of 65.9, was evaluated.
[0382] For the ESBL-negative isolates, the percentage of simulated
patients that attained the above-described TOL targets during the
dosing interval at steady-state for TOL/TAZ MIC values (0.06 to
.gtoreq.32 mg/L) was determined for each TOL/TAZ dosing regimen
within each renal function group.
[0383] For ESBL-positive isolates, a multi-step, sequential
algorithm was used to assess PK-PD target attainment by MIC value
for each TOL/TAZ dosing regimen evaluated within each renal
function group, which took into account both TOL and TAZ PK-PD
target attainment.
Results
[0384] Results of the PK-PD target attainment analysis for TOL/TAZ
1000/500 mg q8h are shown in FIG. 34. Similar such data for
simulated patients following administration of TOL/TAZ 2000/1000 mg
q8h dosing regimens are shown in FIG. 35.
[0385] Potential PK-PD cutoff values based on a threshold of
.gtoreq.80% PK-PD target attainment are provided in Table 32,
stratified by dosing regimen and renal impairment category
[0386] In order to achieve percent probabilities of PK-PD target
attainment by MIC of .gtoreq.90%, PK-PD MIC cut-off values would
decrease by two dilution steps.
TABLE-US-00039 TABLE 32 PK-PD MIC Cut-Off Values Based Upon
Achieving Percent Probabilities Target Attainment by MIC Of
.gtoreq.80% For TOL/TAZ Dosing Regimens Against Enterobacteriaceae
by Renal Function Category Percentage of simulated patients TOL/TAZ
achieving Renal function dosing regimen MIC free-drug % T > MIC
category.sup.a (mg).sup.b (mg/L) targets
.gtoreq.24.8/.gtoreq.32.2.sup.c,d High normal 1000/500 2 80.8/79.3
2000/1000 4 83.0/81.1 Normal 1000/500 4 81.6/80.9 2000/1000 8
82.4/81.6 Mild 1000/500 8 81.5/81.1 2000/1000 16 80.4/80.2 Moderate
500/250 8 80.1/79.4 1000/500 8 85.6/85.6 Severe 250/125 4 84.6/84.6
500/250 8 85.3/85.2 .sup.aRenal function categories were defined as
follows: high normal renal function = creatinine clearance (CLcr)
<150 to .ltoreq.200 mL/min; normal renal function = CLcr <90
to .ltoreq.150 mL/min; mild renal impairment = CLcr <50 to
.ltoreq.90; moderate renal impairment = CLcr .ltoreq.29 to
.ltoreq.80; severe renal impairment = CLcr .ltoreq.15 to <29.
.sup.bTOL/TAZ administered via 1 h intravenous infusion: Q8h.
.sup.cA free-drug % T > threshold of 65.9 for TAZ was considered
when required for on ESBL-producing isolate. .sup.dRepresents the
highest MIC associated with .gtoreq.80% PK-PD target
attachment.
Conclusion
[0387] The results of the PK-PD target attainment analyses for
1000/500 and 2000/1000 mg TOL/TAZ and dosing regimens adjusted for
renal function provide support for in vitro susceptibility test
interpretive criteria for TOL/TAZ against Enterobacteriaceae.
Example 15: Summary of Modified Methods of Administering
Ceftolozane/Tazobactam in Patients with Mild, Moderate and Severe
Renal Impairment
[0388] Ceftolozane/tazobactam is excreted primarily by the renal
route. Consistent with this observation, population pharmacokinetic
(PPK) analysis showed that clearance from plasma (CL) depends on
CL.sub.CR (creatinine clearance) and that CL.sub.CR is the major
determinant of variability in CL.
[0389] The extent of ceftolozane exposure increases with decreasing
renal function. Although exposure increases with decreasing renal
function, no clinically meaningful differences are observed in the
PK of subjects with mild renal impairment compared to those with
normal renal function, indicating that dosage adjustment is not
required in subjects with mild renal impairment. In subjects with
moderate renal impairment, exposure approximately doubles relative
to that in subjects with normal renal function. The results from a
dedicated study in otherwise healthy subjects with severe renal
impairment demonstrate that exposure in subjects with severe renal
impairment is significantly increased and t1/2 is prolonged (Table
57).
[0390] A Monte Carlo simulation analysis was conducted with
CL.sub.CR cut-offs similar to the Sponsor-proposed cut-off values.
Based on this analysis, a 2-fold and 4-fold dose reduction to 750
and 375 mg ceftolozane/tazobactam administered as an IV 1-hour
infusion every 8 hours in subjects with moderate and severe renal
impairment, respectively, compared to the 1.5 g
ceftolozane/tazobactam dose in subjects with normal renal function,
produces sufficient drug concentrations to cover target pathogens
with a Probability of Target Attainment (PTA) of more than 97% for
a conservative % T>MIC of 40% above an MIC of up to 8 .mu.g/mL.
In general, with an increase in t1/2 as renal function declines,
the PTA is increased.
[0391] Additionally, based on exposure values in subjects with
severe renal impairment, a reduced dose of 375 mg
ceftolozane/tazobactam results in a mean AUC for ceftolozane and
tazobactam of 269 and 26.2 .mu.gh/mL, respectively. For tazobactam,
this estimated exposure from a dose of 125 mg in subjects with
severe renal impairment not on hemodialysis is similar to that
achieved with 500 mg tazobactam in subjects with normal renal
function (23.8 .mu.gh/mL). For ceftolozane, this estimated exposure
(269 .mu.gh/mL) from a dose of 250 mg in subjects with severe renal
impairment is approximately 1.4 fold higher than that achieved with
doses of 1 g ceftolozane in subjects with normal renal function.
This increased ceftolozane exposure is below the mean AUC.tau., ss
of approximately 300 .mu.gh/mL after q8h dosing for 10 days that is
demonstrated to be safe.
[0392] With an increase in t1/2 as renal functional declined, the
accumulation of the M1 metabolite of tazobactam (see, e.g., J Clin
Pharmacol. 1994 December; 34(12):1208-17) increased but metabolite
levels were projected to still remain several fold below that
observed with long-term clinical use of Zosyn (see e.g. Expert
Opinion on Drug Metabolism & Toxicology 2010 6:8,
1017-1031).
[0393] From a recommended dose of 375 mg ceftolozane/tazobactam
every 8 hours, the estimated AUC of the tazobactam M1 metabolite
was higher than that in subjects with normal renal function
receiving 1.5 g ceftolozane/tazobactam. However, the estimated
steady-state Cmax and AUC of the M1 metabolite with the recommended
375 mg every 8 hours ceftolozane/tazobactam dose in subjects with
severe renal impairment is still lower than that from the
clinically recommended dose of Zosyn in subjects with severe renal
impairment (Table 46). Accordingly, the dose in subjects with
severe renal impairment should be reduced to 1/4th (i.e., 375 mg
ceftolozane/tazobactam every 8 hours) of that in subjects with
normal renal function.
TABLE-US-00040 TABLE 33 Geometric Mean (CV %) Pharmacokinetic
Parameters After an Intravenous 1-Hour Infusion in Subjects with
Mild, Moderate, and Severe Renal Impairment, and Subjects (Subjects
with Infection and Healthy Volunteers) with Normal Renal Function
Study CXA- Study CXA-201-02 Study CXA-101-02 REN-11-01 Normal Mild
Normal Mild Normal Moderate.sub.(a) Severe.sub.(a)
Ceftolozane/Tazobactam Dose (mg): 1000/0 1000/0 1000/500 1000/500
1000/500 500/250 250/125 Ceftolozane PK C.sub.max (.mu.g/mL) 68.2
(22) 72.1 (24) 76.0 (13) 98.7 (25) 76.1 (52) 42.5 (25) 24.3 (28)
AUC.sub..infin. (.mu.g h/mL) 219 (15) 243 (17) 244 (21) 307 (11)
224 (26) 278 (38) 263 (23) t.sub.1/2 (h) 2.74 (7) 2.97 (14) 3.21
(5) 3.24 (11) 2.92 (17) 5.85 (45) 10.9 (24) Tazobactam PK C.sub.max
(.mu.g/mL) NA NA 16.4 (9) 22.1 (16) 20.0 (28) 13.2 (7) 7.45 (22)
AUC.sub..infin. (.mu.g h/mL) NA NA 26.8 (17) 34.5 (14) 32.4 (16)
32.4 (21) 25.4 (27) t.sub.1/2 (h) NA NA 1.04 (25) 1.16 (22) 1.04
(25) 1.78 (20) 2.5 (22) Tazobactam M1 Metabolite C.sub.max
(.mu.g/mL) NA NA 0.79 (15) 1.2 (15) 1.06 (44) 1.5 (91) 1.1 (20)
AUC.sub..infin. (.mu.g h/mL) NA NA 8.57 (23) 11.6 (8) 9.7 (41) 22.6
(101) 29.0 (30) t.sub.1/2 (h) NA NA 4.12 (14) 4.0 (8) 3.43 (22)
6.67 (27) 11.6 (29) Abbreviations: AUC.sub..infin. = area under the
plasma concentration-time curve from time zero to infinity;
C.sub.max = maximum (peak) plasma drug concentration; t.sub.1/2 =
elimination half-life; TAZ = tazobactam; TOL = ceftolozane Note:
For Study CXA-101-02: normal impairment = CL.sub.CR >80 mL/min
and mild impairment = CL.sub.CR .gtoreq.50 to .ltoreq.80 mL/min;
for Study CXA-201-02: mild impairment = CL.sub.CR .gtoreq.50 to
.ltoreq.80 mL/min and moderate impairment = CL.sub.CR .gtoreq.30 to
<50 mL/min; for Study CXA-REN-11-01: severe impairment =
CL.sub.CR <30 mL/min. .sub.(a)Data are dose normalized to
recommended dose for a 2- and 4-fold dose reduction in moderate and
severe renal impairment, respectively, relative to that in subjects
with normal renal function
TABLE-US-00041 TABLE 34 Recommended Dosing of
Ceftolozane/Tazobactam in Subjects with Renal Insufficiency (as
Total g Ceftolozane/Tazobactam) Creatinine Renal Impairment
Clearance Recommended Dose of Frequency of Category (mL/min)
Ceftolozane/Tazobactam Dosing Normal and Mild >50 1.5 g q8h
Moderate 30-50 750 mg.sup.(a) q8h Severe 15-29 375 mg.sup.(b) q8h
ESRD on HD <15 750 mg.sup.a loading dose q24h immediately
following the first dialysis followed by 450 mg.sup.(c) maintenance
dose q24h Abbreviations: ESRD = end-stage renal disease; HD =
hemodialysis; qxh = every x hours .sup.(a)500/250 mg
ceftolozane/tazobactam .sup.(b)250/125 mg ceftolozane/tazobactam
.sup.(c)300/150 mg ceftolozane/tazobactam
TABLE-US-00042 TABLE 35 Probability of Target Attainment Rates for
40% T > MIC based on MIC levels of 8 .mu.g/mL for Various
Assumptions on Dose, Dosing Interval, and Renal Function
Ceftolozane/ Dosing 40% Tazobactam (mg) Interval (h) T > MIC
Normal Renal Function (CL.sub.CR .gtoreq.90 mL/min) 250/125 8 10.9
500/250 8 68.0 1000/500 8 97.6 250/125 12 0.4 500/250 12 15.9
1000/500 12 63.4 Mild Renal Impairment (CL.sub.CR 50-89 mL/min)
250/125 8 50.6 500/250 8 98.2 1000/500 8 100 250/125 12 7.1 500/250
12 65.3 1000/500 12 94.5 Moderate Renal Impairment (CL.sub.CR 30-49
mL/min) 250/125 8 90.6 500/250 8 100 1000/500 8 100 250/125 12 38.4
500/250 12 94.9 1000/500 12 99.2
TABLE-US-00043 TABLE 35 Probability of Target Attainment Rates for
40% T > MIC based on MIC levels of 8 .mu.g/mL for Various
Assumptions on Dose, Dosing Interval, and Renal Function
(Continued) Ceftolozane/ Dosing 40% Tazobactam (mg) Interval (h) T
> MIC Severe Renal Impairment (CL.sub.CR <30 mL/min) 250/125
8 99 500/250 8 100 1000/500 8 100 250/125 12 81.5 500/250 12 99.5
1000/500 12 100 Abbreviations: % T > MIC = time as percentage of
dosing interval the drug concentration exceeds the MIC; MIC =
minimum inhibitory concentration
TABLE-US-00044 TABLE 36A Mean (CV %) Pharmacokinetic Parameters
After Intravenous 1-hour Infusion of Ceftolozane/Tazobactam in
Subjects with Severe Renal Impairment and Healthy Subjects with
Normal Renal Function Severe Renal Impairment.sub.(a) Healthy
Subjects CXA-REN-11-01.sup.b CXA-QT-10-02 CXA-MD-11-07 (n = 6) (n =
51) (n = 7) Ceftolozane/Tazobactam dose: Analyte 250/125 mg
1000/500 mg 2000/1000 mg PK Parameters Single Dose Single Dose q8h
Ceftolozane C.sub.max (.mu.g/mL) 25 (28) 66.5 (19) 112 (13) AUC
(.mu.g h/mL) 269 (23).sup.c 186 (18).sup.b 300 (10).sub.(d)
t.sub.1/2 (h) 11.1 (24) 2.29 (15) 2.8 (14) Tazobactam C.sub.max
(.mu.g/mL) 7.6 (22) 18.6 (23) 25.8 (15) AUC (.mu.g h/mL) 26.2
(27).sup.b 23.8 (24).sup.b 40.5 (13).sup.c t.sub.1/2 (h) 2.6 (22)
0.870 (18) 1.0 (18) Tazobactam M1 metabolite C.sub.max (.mu.g/mL)
1.1 (20) 1.02 (54) 1.8 (20) AUC (.mu.g h/mL) 26.9 (29).sup.b 7.92
(47).sup.b 11.9 (19).sup.c t.sub.1/2 (h) 12 (29) 3.24 (29) 4 (8)
Abbreviations: AUC = area under the plasma concentration-time
curve; AUC.sub..infin. = area under the plasma concentration-time
curve from time zero to infinity; AUC.sub..tau. ss = area under the
plasma concentration-time curve for a dosing interval (8 hours) at
steady state; C.sub.max = maximum (peak) plasma drug concentration;
q8h = every 8 hours; t.sub.1/2 = elimination half-life: time
required for a 50% decrease in the concentration of the drug
.sub.(a)Severe renal impairment = CL.sub.CR <30 mL/min.
.sup.bEstimated from a dose of 750 mg ceftolozane/tazobactam
assuming linear pharmacokinetics. .sup.cAUC.sub..infin. from a
single dose .sub.(d)AUC.sub..tau. ss at steady-state on Day 10
TABLE-US-00045 TABLE 36B Mean (CV %) Plasma Tazobactam M1
Metabolite Pharmacokinetic Parameters Comparison in Subjects with
Severe Renal Impairment: 2.250 g Zosyn versus 250/125 mg
Ceftolozane/Tazobactam Tazobactam M1 metabolite Zosyn.sub.(a)
Ceftolozane/tazobactam.sub.(b) PK parameters (2.25 g) (250/125 mg)
C.sub.max (.mu.g/mL) 5.2 (30) 1.1 (20) AUC.sub..infin. (.mu.g h/mL)
192 (66) 26.9 (29) Abbreviations: AUC.sub..infin. = area under the
plasma concentration-time curve from time zero to infinity;
C.sub.max = maximum (peak) plasma drug concentration; PK =
pharmacokinetic .sub.(a)AUC.sub..infin. and C.sub.max for a
tazobactam dose of 375 mg from Zosyn (3.375 g) dose normalized to
Zosyn dose of 2.25 g in severe renal impairment .sub.(b)From Study
CXA-REN-11-01; Estimated from a dose of 750 mg
ceftolozane/tazobactam assuming linear PK
Example 16: Pharmacokinetics of CXA-101, Tazobactam, and the M-1
Metabolite of Tazobactam in Subjects with End Stage Renal Disease
on Hemodialysis
[0394] The plasma concentration versus time plots for CXA-101,
tazobactam, and the M-1 metabolite during non-HD on Study Day 1 for
subjects with ESRD are shown in FIGS. 36, 37, and 38, respectively.
The 0.5 and 1.0 hour plasma samples of two subjects (Subject
001-0201 and Subject 001-0205) appeared to have been mislabeled,
since a higher concentration of CXA-101 and tazobactam were seen at
0.5 hours than at 1.0 hour. However, since this did not affect the
PK parameters (AUC, CL etc.) to a substantial degree, the
concentrations were used as reported. The concentrations of CXA-101
appeared to decline in a bi-exponential manner in most subjects and
were above the LLOQ for the entire duration of the sampling
interval. The concentrations of tazobactam were above the
quantifiable limits for between 12 and 48 hours post-dose
administration and appeared to decline in a bi-exponential manner.
The plasma concentrations of the M-1 metabolite increased in plasma
but did not appear to decline at the end of the sampling interval.
Therefore, no PK parameters (AUC, t.sub.1/2) for the M-1 metabolite
were calculated.
[0395] The PK parameters for CXA-101, tazobactam, and the M-1
metabolite during non-HD for subjects with ESRD are presented in
Table 37 below. The median C.sub.max of CXA-101 and tazobactam in
plasma were 44.2 .mu.g/mL and 20.2 .mu.g/mL, respectively. The
median elimination half-lives of CXA-101 and tazobactam were 40.5
and 4.21 hours, respectively. Since the sampling for CXA-101 was
conducted over a period of 48 hours, which is approximately 1
half-life, the estimates of t.sub.1/2, CL, and V.sub.ss parameters
for CXA-101 should be interpreted with caution.
TABLE-US-00046 TABLE 37 Median (Range) Pharmacokinetic Parameters
for CXA-101, Tazobactam, and the M-1 Metabolite of Tazobactam
During Non-Hemodialysis Following Administration of the First Dose
of CXA-201 on Study Day 1 in Subjects with ESRD Parameter (Units)
CXA-101 Tazobactam M-1 Metabolite Half-Life (hr) 40.5 (20.8-58.1)
4.21 (3.38-9.10) ND C.sub.max (.mu.g/mL) 44.2 (30.2-60.6) 20.2
(15.9-30.3) 10.1 (2.9-14.2) T.sub.max (hr) 1.0 (0.5-1.0) 1.0
(0.5-1.0) 30.0 (12.0-48.0) AUC.sub.0-t 903 (372-1233) 107
(45.3-169) 389 (99.8-538) (.mu.g*hr/mL) AUC.sub.0-.infin. 1629
(466-2750) 109 (46.0-170) ND (.mu.g*hr/mL) CL (L/hr) 0.3 (0.2-1.1)
2.4 (1.5-5.4) ND V.sub.ss (L) 17.9 (11.9-31.7) 15.2 (11.5-27.1) ND
ND = Not determined
[0396] Since insufficient urine samples were collected following
the administration of the first dose of study drug on Study Day 1
and over a limited time period, no analysis to determine the amount
of CXA-101, tazobactam, and the M-1 metabolite excreted in the
urine was conducted. Consequently, the CL.sub.R of CXA-101 and
tazobactam in these subjects could not be determined.
[0397] The plasma concentration versus time profiles for CXA-101,
tazobactam, and the M-1 metabolite in subjects with ESRD during HD
following the second dose of study drug are presented in FIGS. 39,
40, and 41, respectively. Dialysis started 2 hours post-start of
the infusion of study drug and lasted for 3 or 4 hours, depending
on the subject. The concentrations of the 3 analytes increased
following the start of the infusion and declined rapidly at the
start of dialysis. The concentrations continued to decline during
dialysis and rebounded slightly at the end of dialysis followed by
a slow decline over the remainder of the sampling interval.
[0398] The plasma PK parameters for CXA-101, tazobactam, and the
M-1 metabolite for subjects with ESRD during HD are summarized in
Table 38 below. Sampling continued beyond a second HD session, but
only plasma concentrations of samples collected between one
dialysis period (0-44 hours) were used in the determination of the
PK parameters. The median C.sub.max for CXA-101, tazobactam, and
the M-1 metabolite were 41.1, 14.9, and 10.9 .mu.g/mL,
respectively. The median elimination half-life of CXA-101 in these
subjects was 43.2 hours. Since sampling was conducted for
approximately 1 half-life, other PK parameters such as
AUC.sub.0-.infin., CL, and V.sub.ss are not reported. Due to the
nature of the plasma concentration versus time profile, the PK
parameters for the M-1 metabolite (t.sub.1/2 and AUC) were not
calculated.
TABLE-US-00047 TABLE 38 Median (Range) Pharmacokinetic Parameters
for CXA-101, Tazobactam, and the M-1 Metabolite of Tazobactam
Following Administration of the Second Dose of CXA-201 on Study Day
4 in Subjects with ESRD During HD Parameter (Units) CXA-101
Tazobactam M-1 Metabolite Half-Life 43.2 (32.8-56.9) 5.0 (1.9-8.5)
368.4.sup.a (hr) C.sub.max 41.1 (17.5-56.4) 14.9 (7.2-22.9) 10.9
(2.2-15.7) (.mu.g/mL) T.sub.max (hr) 1.0 (1.0-1.0) 1.0 (1.0-1.0)
1.5 (0.5-24.0) AUC.sub.0-t 298 (179-437) 37.1 (19.9-57.8) 181.8
(78.0-254.8) (.mu.g*hr/mL) .sup.aBased on data from 1 subject.
[0399] A separate analysis was conducted to determine the PK
parameters of CXA-101, tazobactam, and the M-1 metabolite from the
start of the second study drug infusion to the end of dialysis.
This was conducted in order to determine the contribution of HD on
the removal of the 3 analytes. The plasma concentration versus time
profiles for CXA-101, tazobactam, and the M-1 metabolite during
this period are shown in FIGS. 42, 43 and 44, respectively.
[0400] The PK parameters for CXA-101, tazobactam, and the M-1
metabolite following administration of the second dose of CXA-201
on Study Day 4 for subjects with ESRD during HD are presented in
Table 39 below. Concentrations of CXA-101, tazobactam, and the M-1
metabolite declined rapidly following the start of dialysis with a
median half-life of 1.13, 0.91, and 1.80 hours, respectively.
Maximum concentrations of the 3 analytes decreased rapidly during
HD indicating that greater than 90% of the administered dose was
removed by dialysis. The concentrations at the last sampled
time-point before the end of dialysis, C.sub.last, were
approximately 14-, 32-, and 26-fold lower, respectively, than the
concentrations seen at C.sub.max, indicating a significant
contribution of dialysis in the removal of the administered
dose.
TABLE-US-00048 TABLE 39 Median (Range) of Pharmacokinetic
Parameters for CXA-101, Tazobactam, and the M-1 Metabolite of
Tazobactam Following Administration of the Second Dose of CXA-201
on Study Day 4 in Subjects with ESRD During HD (Start of
Infusion-End of Dialysis) Parameter CXA-101 Tazobactam M-1
Metabolite Half-Life (hr) 1.13 (0.89-1.79) 0.91 (0.66-1.35) 1.80
(0.68-2.38) C.sub.max (.mu.g/mL) 41.1 (17.5-56.4) 14.9 (7.19-22.9)
10.9 (1.26-15.7) T.sub.max (hr) 1 (1-1) 1.00 (1.00-1.00) 1.50
(0.50-1.50) C.sub.last (.mu.g/mL) 2.88 (1.23-4.48) 0.46 (0.13-1.14)
0.41 (0.26-1.11) AUC.sub.0-t 97.1 (39.2-115) 28.9 (14.0-44.0) 26.8
(3.77-32.0) (.mu.g*hr/mL) AUC.sub.0-.infin. 99.8 (46.9-122) 29.4
(15.7-45.2) 31.0 (23.4-34.9) (.mu.g*hr/mL) CL.sub.ss (L/hr) 5.01
(4.11-10.7) 8.53 (5.53-15.9) ND V.sub.ss (L) 7.26 (5.71-20.5) 10.4
(6.61-25.1) ND ND = Not determined
[0401] The summary of CL.sub.D of CXA-101, tazobactam, and M-1
metabolite in subjects with ESRD during HD is provided in Table 40.
Briefly, the total amount of analyte recovered in the dialysate was
computed and the ratio of the total amount recovered in the
dialysate and the plasma AUC during the period of dialysis yielded
the CL.sub.D. Dialysate concentrations and the corresponding
volumes were available from 0-3 hours in Subject 001-0201, Subject
001-0202, and Subject 001-0204. In these subjects, the plasma AUC
from 0-3 hours was used in the computation of the CL.sub.D. In the
remaining three subjects, plasma AUC from 0-4 hours was
utilized.
[0402] The median CL.sub.D for CXA-101, tazobactam, and the M-1
metabolite was 5.75, 4.39, and 4.59 L/hr, respectively. In 3
subjects (Subjects 001-0201, 001-0202, and 001-0204), the
cumulative amounts of CXA-101 recovered in the dialysate were
greater than the administered dose. The total volumes of dialysate
collected are an approximation. Any differences in the volume of
dialysate collected can impact the calculated recovery of the drug
from the dialysate. Additionally, since the plasma concentrations
reflect any carryover from the previously administered dose on Day
1, the amount in the dialysate can fluctuate significantly.
TABLE-US-00049 TABLE 40 Summary of Dialysis Clearance for CXA-101,
Tazobactam, and the M-1 Metabolite of Tazobactam Following
Hemodialysis in Subjects with ESRD on HD (Median and Range) Dose
Amount in AUC.sub.t0-t1 CL.sub.D Analyte (mg) Dialysate (mg)
(.mu.g*hr/mL) (L/hr) CXA-101 500 438 (131-709) 87 (39-102) 5.75
(1.78-8.88) Tazobactam 250 111 (33-185) 26.4 (13.9-40.5) 4.39
(1.36-6.29) M-1 Metabolite -- 136 (36-220) 27.5 (3.8-32.7) 4.59
(1.44-11.6)
[0403] The percent reduction in plasma concentrations for CXA-100,
tazobactam, and the M-1 metabolite and is shown in Table 41 below.
The median RDHD for CXA-101, tazobactam, and the M-1 metabolite was
92%, 95%, and 93%, respectively, indicating significant removal by
HD.
TABLE-US-00050 TABLE 41 Summary of Percent of CXA-101, tazobactam,
and the M-1 Metabolite of Tazobactam Removed During Hemodialysis in
Subjects with ESRD on HD (Median and Range) Concentration
Concentration before HD after HD Change in Percent Analyte
(.mu.g/mL) (.mu.g/mL) Concentration Removed CXA-101 34.4
(13.2-49.3) 2.9 (1.2-4.5) 32.3 (10.2-44.8) 91.5 (72.3-96.3)
Tazobactam 10.8 (3.9-18.7) 0.5 (0.1-1.1) 10.5 (3.6-17.6) 95.3
(83.8-98.6) M-1 Metabolite 9.4 (1.4-14.9) 0.4 (0.3-1.1) 9.1
(0.5-14.5) 93.4 (38.1-97.7)
[0404] Any patent, patent application, publication, or other
disclosure material identified in the specification is hereby
incorporated by reference herein in its entirety. Any material, or
portion thereof, that is said to be incorporated by reference
herein, but which conflicts with existing definitions, statements,
or other disclosure material set forth herein is only incorporated
to the extent that no conflict arises between that incorporated
material and the present disclosure material.
* * * * *