Sex differences in atazanavir pharmacokinetics and associations with time to clinical events: AIDS Clinical Trials Group Study A5202.

TitleSex differences in atazanavir pharmacokinetics and associations with time to clinical events: AIDS Clinical Trials Group Study A5202.
Publication TypeJournal Article
Year of Publication2014
AuthorsVenuto CS, Mollan K, Ma Q, Daar ES, Sax PE, Fischl M, Collier AC, Smith KY, Tierney C, Morse GD
JournalJ Antimicrob Chemother
Volume69
Issue12
Pagination3300-10
Date Published2014 Dec
ISSN1460-2091
KeywordsAdult, Anti-HIV Agents, Atazanavir Sulfate, Female, HIV Infections, Humans, Male, Metabolic Clearance Rate, Middle Aged, Oligopeptides, Plasma, Pyridines, Ritonavir, Sex Characteristics, Time Factors, Treatment Failure, Treatment Outcome
Abstract

OBJECTIVES: It is uncertain whether HIV-1 antiretroviral exposure and clinical response varies between males and females or different race/ethnic groups. We describe ritonavir-enhanced atazanavir pharmacokinetics in relation to virological failure, safety and tolerability in treatment-naive individuals to investigate potential differences.

METHODS: Plasma samples were collected from participants in AIDS Clinical Trials Group Study A5202 for measurement of antiretroviral concentrations. Individual estimates of apparent oral clearance of atazanavir (L/h) were calculated from a one-compartment model and divided into tertiles as slow (<7), middle (7 to <9; reference group) and fast (≥9). Associations between atazanavir clearance and clinical outcomes were estimated with a hazard ratio (HR) from Cox proportional hazards models. Interactions between atazanavir clearance and sex, race/ethnicity and NRTIs were investigated for each of the outcomes.

RESULTS: Among 786 participants, average atazanavir clearance was slower in females (n = 131) than males (n = 655). Atazanavir clearance was associated with time to virological failure (P = 0.053) and this relationship differed significantly by sex (P = 0.003). Females in the fast atazanavir clearance group had shorter time to virological failure (HR 3.49; 95% CI 1.24-9.84) compared with the middle (reference) atazanavir clearance group. Among males, the slow atazanavir clearance group had a higher risk of virological failure (HR 2.10; 95% CI 1.16-3.77).

CONCLUSIONS: Atazanavir clearance differed by sex. Females with fast clearance and males with slow clearance had increased risk of virological failure.

DOI10.1093/jac/dku303
Alternate JournalJ. Antimicrob. Chemother.
PubMed ID25159623
PubMed Central IDPMC4228779
Grant ListAI069434 / AI / NIAID NIH HHS / United States
AI069477 / AI / NIAID NIH HHS / United States
AI38855 / AI / NIAID NIH HHS / United States
AI38858 / AI / NIAID NIH HHS / United States
AI68634 / AI / NIAID NIH HHS / United States
AI68636 / AI / NIAID NIH HHS / United States
P30 AI50410 / AI / NIAID NIH HHS / United States
T32 NS007338 / NS / NINDS NIH HHS / United States
T32 NS007338 / NS / NINDS NIH HHS / United States
U01AI068636 / AI / NIAID NIH HHS / United States
UL1 TR000439 / TR / NCATS NIH HHS / United States
UM1 AI068634 / AI / NIAID NIH HHS / United States
UM1 AI068636 / AI / NIAID NIH HHS / United States
UM1 AI069412 / AI / NIAID NIH HHS / United States
UM1 AI069424 / AI / NIAID NIH HHS / United States
UM1 AI069477 / AI / NIAID NIH HHS / United States
UM1 AI069511 / AI / NIAID NIH HHS / United States
UM1 AI106701 / AI / NIAID NIH HHS / United States
UM1AI106701-01 / AI / NIAID NIH HHS / United States