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Pharmacokinetic Profile of Darunavir (DRV) Co-Administered With Low-Dose Ritonavir (DRV/r) in Treatment-Experienced Women and Men With HIV Infection: 4-Week Analysis in a Substudy of the GRACE
(Gender, Race, and Clinical Experience) Study
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Reported by Jules Levin
9th International Workshop on Clinical Pharmacology of HIV Therapy
April 7-9, 2008
New Orleans
Vanitha Sekar, PhD1; Robert Ryan, MS1; Deborah Schaible, PharmD2; Amy
Mazikewich, PharmD2; Joseph Mrus, MD, MSc2
1Tibotec, Inc., Yardley, PA, USA; 2Tibotec Therapeutics, Bridgewater, NJ, USA
Introduction to GRACE
GRACEa is the largest treatment trial to date in the US to focus on women with HIV, and the first treatment trial to focus on treatment-experienced women with HIV in North America
GRACE is a multi-center, open-label phase IIIb trial designed to assess sex and race differences in efficacy, safety, and tolerability of darunavir/ritonavir (DRV/r) over 48 weeks in treatment-experienced patients
Final enrollment figures for GRACE (N=429):
-- 287 (67%) women and 142 (33%) men
-- 265 (62%) black, 96 (22%) Hispanic, 65 (15%) white, and 3 (1%) other
AUTHOR SUMMARY
Preliminary GRACE PK Sub-study Findings: Conclusions from Week 4
At Week 4, in this subset of predominantly non-white, treatment-experienced HIV patients from the GRACE study:
-- Median exposure to DRV (AUC12h) was approximately 20% higher in women compared with men
-- Median exposure to RTV (AUC12h) was approximately 70% higher in women compared with men
-- Median exposure to DRV and RTV was similar in black and Hispanic patients
DRV PK results were consistent with those of previous studies
Further study is warranted to better understand sex-related differences in RTV exposure
Clinical relevance of these findings will be assessed at study conclusion (Week 48)
Rationale for GRACE Pharmacokinetic (PK) Sub-study
The POWER and TITAN studies evaluated the safety and tolerability of DRV/r plus OBR in HIV-1-infected, treatment-experienced patients
-- PK analyses suggested that exposure to DRV was higher in women than in men, but this difference was not considered clinically relevant1,2
-- No clinically relevant differences in safety and efficacy by sex or race were observed
POWER and TITAN study populations were predominantly male and white
-- Further investigation of the impact of sex and race on DRV PK is warranted
This sub-study examines the PK of DRV and RTV in a subset of predominantly non-white patients enrolled in GRACE
-- Population PK parameter estimates for DRV will be obtained for all subjects participating in GRACE
Based on individual plasma concentration-time data, using actual sampling times,
the following PK parameters for DRV and RTV were evaluated:
-- Pre-dose plasma concentration (C0h)
-- Maximum plasma concentration (Cmax)
-- Area under the plasma concentration-time curve at 12 hours (AUC12h)
GRACE PK Sub-study Methods
All subjects received DRV/r 600/100 mg bid plus OBR
Medications administered 30 minutes following a full breakfast
-- Subjects fasted for ≥10 hours prior to breakfast (water allowed)
Plasma concentrations of DRV and RTV determined by validated analytical methods
-- Non-compartmental analyses for DRV and RTV performed using WinNonlin Professional (Pharsight Corporation, Mountain View, CA, USA)
PK evaluations reported after 4 weeks of therapy
-- 17 women and 11 men were evaluable at Week 4
-- Additional data will be available at Week 24 and Week 48
GRACE PK Sub-study: Baseline Demographics
Of note, 63% of women were black and 28% Hispanic. Baseline median weight was 81 kg and BMI was 28.6 kg/m2. Viral load mean 4.7 logs and median CD4 was 167.
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