title: Sex differences in atazanavir pharmacokinetics and associations with time to clinical events: AIDS Clinical Trials Group Study A5202.
abstract: OBJECTIVE
  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.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Venuto
authors.forename: Katie
authors.initials: K
authors.lastname: Mollan
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
authors.forename: Eric S
authors.initials: ES
authors.lastname: Daar
authors.forename: Paul E
authors.initials: PE
authors.lastname: Sax
authors.forename: Margaret
authors.initials: M
authors.lastname: Fischl
authors.forename: Ann C
authors.initials: AC
authors.lastname: Collier
authors.forename: Kimberly Y
authors.initials: KY
authors.lastname: Smith
authors.forename: Camlin
authors.initials: C
authors.lastname: Tierney
authors.forename: Gene D
authors.initials: GD
authors.lastname: Morse
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000069446:Atazanavir Sulfate; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D010949:Plasma / Q000737:chemistry; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects; D012727:Sex Characteristics; D013997:Time Factors; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D019438:Ritonavir
keywords: clearance; efficacy; safety; tolerability