Indication:
Antiretroviral
Protocol No.:
AI424106
Phase:
1
Study Initiation Date:
4-Sep-2006
Study Completion Date: 18-Nov-2006
Report Date:
20-Aug-2007
EFFECT OF ATAZANAVIR ADMINISTERED WITH AND WITHOUT
RITONAVIR ON THE PHARMACOKINETICS OF A CYTOCHROME P450 2C8
SUBSTRATE ROSIGLITAZONE IN HEALTHY SUBJECTS
This document is a confidential communication of Bristol-Myers Squibb Company. Acceptance of this
document constitutes an agreement by the recipient that no unpublished information contained herein will
be published or disclosed without Bristol-Myers Squibb Company's prior written approval, except that this
document may be disclosed to appropriate Institutional Review Committees so long as they are requested to
keep it confidential. This study was conducted in accordance with Good Clinical Practice.
Name and Affiliation of Principal or coordinating Investigators or name and address of
sponsor’s responsible medical officer:
Investigator:
Tong Li, MD
Bristol-Myers Squibb Clinical Research Center
3 Hamilton Health Place
Hamilton, NJ 08690
Company Signatory:
Dennis M. Grasela, Pharm D, PhD
Bristol-Myers Squibb
Princeton, NJ 08543-4000
Tel: 609-252-5487
Fax: 609-252-7034
Department of Clinical Discovery
Bristol-Myers Squibb Research and Development
Bristol-Myers Squibb Company
Princeton, NJ 08543-4000
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FINAL REPORT SYNOPSIS
TITLE OF STUDY: Effect of Atazanavir Administered with and without Ritonavir on the
Pharmacokinetics of a Cytochrome P450 2C8 Substrate Rosiglitazone in Healthy Subjects
INVESTIGATORS: Tong Li, MD
STUDY CENTERS: BMS Clinical Research Center, Three Hamilton Health Place, Hamilton, NJ
PUBLICATIONS:
None
STUDY PERIOD:
Date first subject enrolled: 4-Sep-2006
Date last subject completed: 18-Nov-2006
CLINICAL PHASE: 1
OBJECTIVES:
Primary Objective: To assess the effect of atazanavir (ATV) 400 mg QD and ATV/ritonavir (RTV)
300/100 mg QD at steady state on the single dose pharmacokinetics of the CYP2C8 probe rosiglitazone
(RGZ).
Secondary Objectives:
•
To assess the safety and tolerability of RGZ and ATV coadministration with and without RTV
•
To explore the relationship between ATV exposure, CYP2C8 genotype and pharmacokinetics of
RGZ.
METHODOLOGY This was a non-randomized, open-label, single-sequence crossover design study in
healthy subjects. Subjects were screened to determine eligibility within 21 days prior to study drug
administration on Day 1. Subjects were admitted to the clinical facility on Day -1 for baseline evaluations
and remained confined until study discharge on Day 18. On the morning of Day 1 (Period 1), subjects were
®
administered a single 4-mg dose of RGZ (Avandia , rosiglitazone maleate) (Treatment A). In Period 2,
subjects were administered ATV 400 mg QD (Treatment B) on Days 2 to 6. On Day 7, ATV 400 mg QD
was coadministered with a 4-mg dose of RGZ (Treatment C). In Period 3, subjects were administered
ATV/RTV 300/100 mg QD (Treatment D) on Days 8 to 16. On Day 17, subjects were coadministered
ATV/RTV 300/100 mg QD with a 4-mg dose of RGZ (Treatment E). All doses of study medication were
given in the morning within approximately 5 minutes of completing a light meal. Subjects were discharged
from the study on Day 18, after all safety assessments and pharmacokinetic (PK) sample collections were
completed. Serial blood samples for PK analysis were collected up to 24 hours postdose on Days 1, 7, and
17. Serial blood samples for ATV and RTV PK were collected up to 24 hours postdose on Days 7 (ATV
only) and 17 (ATV and RTV). The PK profiles of RGZ obtained for Treatments A, C, and E were to be
compared. A blood sample was collected for CYP2C8 genotyping of all subjects.
Physical examinations, vital sign measurements, 12-lead electrocardiogram (ECG), and clinical laboratory
evaluations were performed at selected times throughout the study. Subjects were closely monitored for
adverse events (AEs) throughout the study.
NUMBER OF SUBJECTS: A total of 22 subjects were enrolled, 14 were treated in this study and 8
subjects were not treated (no longer met study criteria or were not needed). All 14 treated subjects
completed the study.
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MAIN CRITERIA FOR INCLUSION: Healthy subjects as determined by medical history, physical
examination, 12-lead ECGs, and clinical laboratory evaluations were eligible to participate in the study.
Women of childbearing potential (WOCBP) were to be using an adequate method of contraception to avoid
pregnancy throughout the study and for up to 8 weeks after the study in such a manner that the risk of
pregnancy was minimized. Subjects who were 18-50 years of age with a body mass index (BMI) of 18-32
2
kg/m , inclusive, were eligible.
TEST PRODUCT, DOSAGE FORM AND MODE OF ADMINISTRATION, BATCH NUMBERS:
• Treatment C: Oral ATV 400 mg QD dose and a single oral dose of 4 mg RGZ on Day 7, following oral
ATV 400 mg QD dose administration from Days 2 to 6 (Treatment B).
• Treatment E: Oral ATV/RTV 300/100 mg QD dose and a single oral dose of 4 mg RGZ on Day 17,
following oral ATV/RTV 300/100 mg QD dose administration from Days 8 to 16
(Treatment D).
Atazanavir 150 mg capsules for oral use, Label Batch Number 4B78591, Product Batch Number:
8MBA105.
Atazanavir 200 mg capsules for oral use, Label Batch Number 5K07382, Product Batch Number 5C04946.
The Investigator supplied the marketed drug 100 mg Norvir
®
(Ritonavir, RTV) Lot No. 426632E21.
DURATION OF TREATMENT: Seventeen (17) days. On the morning of Day 1 subjects were
administered a single dose of RGZ 4-mg. On Days 2 to 7, subjects were administered ATV 400 mg QD. A
second dose of 4-mg RGZ was coadministered on Day 7. On Days 8 to 17, subjects were administered
ATV/RTV 300/100 mg QD. A third dose of 4-mg RGZ was coadministered on Day 17.
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS:
•
Treatment A: Single oral dose of 4 mg RGZ on Day 1
The Investigator supplied the marketed drug 4 mg Avandia
®
(RGZ)
Lot No. 6ZP0922.
CRITERIA FOR EVALUATION:
Pharmacokinetic Measures: PK for RGZ, ATV and RTV were derived from plasma concentration versus
time data. The PK parameters assessed included:
Rosiglitazone:
•
Cmax:
Maximum observed concentration on Days 1, 7 and 17
•
Tmax:
Time to reach Cmax on Days 1, 7 and 17
•
AUC(0-T):
Area under the plasma concentration-time curve from zero to the time of the last
quantifiable concentration on Days 1, 7 and 17
•
AUC(INF):
Area under the concentration-time curve, from time zero extrapolated to infinite time on
Days 1, 7 and 17
•
T-HALF:
Elimination half life during a dosing interval on Days 1, 7 and 17
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Atazanavir and Ritonavir:
•
Cmax:
Maximum observed concentration on Days 7 (ATV only) and 17
•
Tmax:
Time to reach Cmax on Days 7 (ATV only) and 17
•
Cmin:
Trough plasma concentration 24 hours post-dose administration on Days 7 (ATV only)
and 17 (Days 8 and 18, respectively)
•
AUC(TAU): Area under the concentration-time curve, in one dosing interval from time zero to
24 hours on Days 7 (ATV only) and 17
•
T-HALF:
Terminal elimination half life on Days 7 (ATV only) and 17
Pharmacodynamic Measures: Not applicable.
Pharmacogenomic Measures: A blood sample was collected from each subject for CYP2C8 genotyping.
Safety Measures: Safety assessments were based on adverse event reports and the results of vital sign
measurements, ECGs, physical examinations and clinical laboratory tests. The incidence of adverse events
were tabulated and reviewed for potential significance and clinical importance.
STATISTICAL METHODS: Sample Size Determination: Although the sample size was not based on
statistical power considerations, 12 evaluable subjects provided at least 86% and 88% confidence that the
estimated ratios of the geometric means for RGZ AUC(INF) and Cmax, respectively, with or without ATV
or ATV/RTV, were within 10% of the true ratios. To allow for dropouts, an adequate number of subjects
were needed to meet the inclusion/exclusion criteria so that up to 14 subjects were dosed on Day 1 in order
to have 14 evaluable subjects at the end of the study.
Statistical Analysis: To assess the effect of ATV 400 mg or of ATV 300 mg co-administered with RTV
100 mg on the PK of RGZ, point estimates and 90% confidence intervals for the ratios of the geometric
means for RGZ Cmax, AUC(0-T) and AUC(INF), with and without ATV or ATV/RTV, were constructed.
These estimates were generated using general linear model analyses of log-transformed data, with
treatment as a fixed effect and measurements within each subject as repeated measurements. Point
estimates and 90% confidence intervals for differences at the log-scale were exponentiated to obtain
estimates and confidence intervals for ratios of geometric means in the original scale. In all comparisons
RGZ (Treatment A) was used as the reference. No adjustments were made for multiplicity.
Summary statistics were provided for all available PK parameters, for all analytes, by treatment.
Geometric means and coefficients of variation were reported for RGZ Cmax, AUC(0-T) and AUC(INF)
and for ATV and RTV Cmax, AUC(TAU) and Cmin. Medians, minima, and maxima were reported for
Tmax. Means and standard deviations were reported for all other PK parameters.
Analysis: Statistical analyses were performed by the Global Biometric Sciences Department of the
Bristol-Myers Squibb Research and Development. All available data from all subjects who received study
medication were included in the summaries of physical examination findings, clinical laboratory data, vital
signs, and AEs.
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PHARMACOKINETIC RESULTS:
noncompartmental analysis.
The PK results were determined using a
validated
The summary statistics for RGZ PK parameters are presented in Table 1.
Table 1. Summary Statistics for RGZ Pharmacokinetic Parameters
Treatment
Pharmacokinetic
A
C
E
N=14
N=14
N=14
248 (20)
267 (20)
242 (19)
1582 (29)
2135 (20)
1312 (18)
1541 (28)
2011 (20)
1298 (17)
1.5 (0.5, 2.5)
2.0 (1.0, 3.0)
2.0 (0.5, 2.0)
4.3 (1.0)
5.7 (1.0)
3.3 (0.6)
Parameter
Cmax (ng/mL)
Geometric Mean (CV%)
AUC(INF) (ng•h/mL)
Geometric Mean (CV%)
AUC(0-T) (ng•h/mL)
Geometric Mean (CV%)
Tmax (h)
Median (Min, Max)
T-HALF (h)
Mean (SD)
Treatments: A=RGZ 4 mg on 1 Day
C=ATV 400 mg QD + RGZ 4 mg on Day 7, following ATV 400 mg QD on Days 2 to 6 (Treatment B)
E=ATV/RTV 300/100 mg QD + RGZ 4 mg on Day 17, following ATV/RTV 300/100 mg QD on Days 8
to 16 (Treatment D)
The geometric means and ratios of geometric means with 90% confidence intervals for RGZ are presented
in Table 2.
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Table 2: Statistical Analyses for RGZ Pharmacokinetic Parameters
Ratios of Geometric Means
Point Estimate (90% CI)
Geometric Means
Pharmacokinetic
Parameter
Treatment
A
Treatment
C
Treatment
E
Cmax (ng/mL)
248
267
242
1.077 (1.029, 1.127)
0.974 (0.912, 1.039)
AUC(INF)
(ng•h/mL)
1582
2135
1312
1.349 (1.262, 1.443)
0.829 (0.771, 0.892)
AUC(0-T)
(ng•h/mL)
1541
2011
1298
1.305 (1.223, 1.392)
0.842 (0.786, 0.902)
Treatments C / A
Treatments E / A
Treatments: A=RGZ 4 mg on 1 Day
C=ATV 400 mg QD + RGZ 4 mg on Day 7, following ATV 400 mg QD on Days 2 to 6 (Treatment B)
E=ATV/RTV 300/100 mg QD + RGZ 4 mg on Day 17, following ATV/RTV 300/100 mg QD on Days 8
to 16 (Treatment D).
Rosiglitazone AUC(INF) and AUC(0-T) increased approximately 35% and 30%, respectively, when RGZ
4 mg was co-administered with ATV 400 mg relative to administration of RGZ 4 mg alone. The 90% CIs
for AUC(INF) were entirely above the upper bound (1.25) of the no-effect interval. Rosiglitazone Cmax
was unchanged as the 90% CI was within the no-effect interval.
Rosiglitazone AUC(INF) and AUC(0-T) decreased approximately 17% and 16%, respectively, when RGZ
4 mg was co-administered with ATV/RTV 300/100 mg relative to administration of RGZ 4 mg alone and
the 90% CIs were entirely below 1.00 and the lower bound was 0.77. Rosiglitazone Cmax was unchanged
as the 90% CI satisfied the no-effect interval.
Sparse samples were collected for ATV and RTV PK and exposures were largely comparable to historical
data.
PHARMACODYNAMIC RESULTS: Not applicable.
PHARMACOGENETICS RESULTS:
The RGZ AUC(INF) values for subjects with CYP2C8*2, CYP2C8*3 or CYP2C8*4 genotypes were
within the range observed in CYP2C8 wild-type subjects after administration of RGZ 4 mg. All subjects
displayed an increase in RGZ AUC with ATV 400 mg co-administration and subjects with CYP2C8*2,
CYP2C8*3 or CYP2C8*4 genotypes displayed RGZ AUC % increases within the range observed in wildtype subjects. Thirteen of the 14 (93%) subjects demonstrated a decrease in RGZ AUC when RGZ 4 mg
was co-administered with steady-state ATV/RTV 300/100 mg. The decrease in RGZ AUC(INF) in subjects
with CYP2C8*2, CYP2C8*3 or CYP2C8*4 genotypes were within the range observed in subjects with
wild-type CYP2C8 genotype. Though the CYP2C8 genotype data are limited, results from the current
study suggest that there is no in vivo relationship between RGZ exposures and CYP2C8 genotype.
Similar trends in RGZ exposure were observed across available CYP2C8 genotypes as indicated in
Figure 1.
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Figure 1:
Individual Rosiglitazone AUC(INF) versus CYP2C8 Genotype
3500
Treatment
TRT A
TRT C
TRT E
Rosiglitazone AUC(0-T) (ng*h/mL)
3250
3000
2750
2500
2250
2000
1750
1500
1250
1000
750
500
wt/wt
*2/*2
Genotype CYP2C8
*3/wt
*4/wt
TRT A = RGZ 4 mg, TRT C = ATV 400 mg QD + RGZ 4 mg, TRT E = ATV/RTV 300/10 mg QD + RGZ 4 mg
Program Source: //wwbmd/clin/proj/ai/424/106/dev/stats/pk_plot_106_rm_pg.sas Run Date/Time: 23May07 8:18
SAFETY AND TOLERABILITY RESULTS: There were no reported serious adverse events (SAEs) in
this study, nor were there any discontinuations due to adverse events (AEs). There were nine (9) AEs
reported and all were mild to moderate in intensity, five (5) of which were related to the intravenous
catheter site. Three AEs were reported as possibly related to drug, 1 mild AE of headache on Treatment D:
ATV/RTV 300/100 mg QD, 1 moderate AE of erythema on Treatment D and 1 mild AE of dyspepsia on
Treatment C: ATV 400 mg QD + RGZ 4 mg. Most AEs were deemed by the Investigator to be unrelated
to the study medication.
Most marked laboratory abnormalities reported in this study were total bilirubin elevations, including
Grade 3/4 abnormalities, which is consistent with that expected with the use of ATV. None were
considered by the Investigator to be AEs.
None of the observed ECG abnormalities were considered clinically significant by the Investigator. There
were no new physical examination findings occurring during the study that were not present prior to the
start of study drug administration.
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CONCLUSIONS:
•
Co-administration of RGZ 4 mg with ATV 400 mg QD resulted in an approximate 35% increase
in RGZ AUC; 90% confidence intervals for RGZ AUC(INF) were entirely above the 0.80 to 1.25
no effect interval. This suggests that atazanavir without RTV is a weak CYP2C8 inhibitor.
•
Co-administration of RGZ 4 mg with ATV/RTV 300/100 mg QD resulted in an approximate 17%
decrease in RGZ AUC; the lower bound of the 90% confidence interval for RGZ AUC(INF) was
0.77. This suggests that low dose RTV appears to induce CYP2C8, offsetting inhibition by ATV.
•
Based on available data, there appeared to be no clear relationship between ATV exposures, RGZ
exposures and CYP2C8 genotype.
•
Co-administration of single doses of RGZ 4 mg with ATV 400 mg and ATV/RTV 300/100 mg at
steady state were generally safe and well-tolerated.
DATE OF REPORT: 20-Aug-2007
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