Abstract | OBJECTIVES: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: Expression of CYP3A5 appears to be associated with increased M1 and M2 atazanavir metabolite formation, without significantly affecting parent compound pharmacokinetics.
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Authors | Jose R Castillo-Mancilla, Christina L Aquilante, Michael F Wempe, Laura M Smeaton, Cynthia Firnhaber, Alberto M LaRosa, Nagalingeswaran Kumarasamy, Adriana Andrade, Gautam Baheti, Courtney V Fletcher, Thomas B Campbell, David W Haas, Samantha MaWhinney, Peter L Anderson |
Journal | The Journal of antimicrobial chemotherapy
(J Antimicrob Chemother)
Vol. 71
Issue 6
Pg. 1609-18
(06 2016)
ISSN: 1460-2091 [Electronic] England |
PMID | 26892777
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]. |
Chemical References |
- Anti-HIV Agents
- HIV Protease Inhibitors
- Atazanavir Sulfate
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Topics |
- Adult
- Anti-HIV Agents
(administration & dosage, pharmacokinetics, pharmacology)
- Atazanavir Sulfate
(administration & dosage, pharmacokinetics, pharmacology)
- Female
- HIV Infections
(drug therapy)
- HIV Protease Inhibitors
- Humans
- Male
- Middle Aged
- Peru
- Pharmacogenetics
- Polymorphism, Genetic
- Retrospective Studies
- South Africa
- United States
- Young Adult
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