title: Pharmacogenetics of unboosted atazanavir in HIV-infected individuals in resource-limited settings: a sub-study of the AIDS Clinical Trials Group (ACTG) PEARLS study (NWCS 342).
abstract: The multinational PEARLS (ACTG A5175) study, conducted mainly in resource-limited settings, identified an increased treatment failure rate among HIV-infected individuals randomized to once-daily unboosted atazanavir, didanosine-EC, and emtricitabine compared with efavirenz-based regimens. We evaluated associations between selected human genetic polymorphisms and atazanavir pharmacokinetics in PEARLS.
  
  
  
  Polymorphisms in CYP3A5, ABCB1, SLCO1B1 and NR1I2 were genotyped in PEARLS participants randomized to atazanavir plus didanosine-EC plus emtricitabine in Peru, South Africa and the USA, who also consented to genetic analysis. Non-linear mixed-effects population pharmacokinetic modelling was used to predict atazanavir oral clearance (CL/F) and concentration at 24 h (C24). Atazanavir mono-oxidation metabolites M1 and M2 were quantified from the same single-point plasma sample used to quantify the parent drug. Data were log10 transformed for statistical analysis using unpaired t-tests and one-way ANOVA and are presented as geometric mean (95% CI).
  
  
  
  Eighty-four HIV-infected participants were genotyped, including 44 Black Africans or African Americans and 28 women. Median age was 34 years. We identified 56 CYP3A5 expressers and 28 non-expressers. Atazanavir CL/F and C24 did not differ between CYP3A5 expressers and non-expressers: 13.2 (12.1-14.4) versus 12.7 L/h (11.7-13.9), P = 0.61, and 75.3 (46.1-123.0) versus 130.9 ng/mL (86.9-197.2), P = 0.14, respectively. M1/atazanavir and M2/atazanavir ratios were higher in expressers than in non-expressers: 0.0083 (0.0074-0.0094) versus 0.0063 (0.0053-0.0075), P = 0.008, and 0.0065 (0.0057-0.0073) versus 0.0050 (0.0042-0.0061), P = 0.02, respectively.
  
  
  
  Expression of CYP3A5 appears to be associated with increased M1 and M2 atazanavir metabolite formation, without significantly affecting parent compound pharmacokinetics.
authors.affiliation: Division of Infectious Diseases, School of Medicine, University of Colorado-AMC, Aurora, CO, USA.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Castillo-Mancilla
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado-AMC, Aurora, CO, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Aquilante
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado-AMC, Aurora, CO, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wempe
authors.affiliation: The Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Smeaton
authors.affiliation: Clinical HIV Research Unit, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Firnhaber
authors.affiliation: Asociación Civil IMPACTA Salud y Educación, Barranco, Lima, Perú
authors.forename: Alberto M
authors.initials: AM
authors.lastname: LaRosa
authors.affiliation: YRG-CARE, Chennai, India.
authors.forename: Nagalingeswaran
authors.initials: N
authors.lastname: Kumarasamy
authors.affiliation: Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Andrade
authors.affiliation: PAREXEL International, Waltham, MA, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Baheti
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Courtney V
authors.initials: CV
authors.lastname: Fletcher
authors.affiliation: Division of Infectious Diseases, School of Medicine, University of Colorado-AMC, Aurora, CO, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Campbell
authors.affiliation: Departments of Medicine, Pharmacology, Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA Meharry Medical College, Nashville, TN, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
authors.affiliation: Department of Biostatistics and Bioinformatics, Colorado School of Public Health, University of Colorado-AMC, Aurora, CO, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: MaWhinney
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado-AMC, Aurora, CO, USA peter.anderson@ucdenver.edu.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Anderson
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000069446:Atazanavir Sulfate / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D010568:Peru; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D013019:South Africa; D014481:United States; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D000069446:Atazanavir Sulfate