TY - JOUR
T1 - Pharmacogenetics of unboosted atazanavir in HIV-infected individuals in resource-limited settings
T2 - A sub-study of the AIDS Clinical Trials Group (ACTG) PEARLS study (NWCS 342)
AU - Castillo-Mancilla, Jose R.
AU - Aquilante, Christina L.
AU - Wempe, Michael F.
AU - Smeaton, Laura M.
AU - Firnhaber, Cynthia
AU - LaRosa, Alberto M.
AU - Kumarasamy, Nagalingeswaran
AU - Andrade, Adriana
AU - Baheti, Gautam
AU - Fletcher, Courtney V.
AU - Campbell, Thomas B.
AU - Haas, David W.
AU - MaWhinney, Samantha
AU - Anderson, Peter L.
N1 - Funding Information:
This work was supported by Award Number U01AI068636 from the National Institute of Allergy and Infectious Diseases and supported by National Institute of Mental Health (NIMH), National Institute of Dental and Craniofacial Research (NIDCR). This work was also supported by NIH/NCRR Colorado CTSI (CCTSI) Grant Numbers UL1 RR025780 and UL1 TR001082; NIH/NIAID ACTG Minority Investigator Award AI0 68636; and NIH/NIAID K23 AI104315. The research utilized services of the Medicinal Chemistry Core Facility (MCCF) housed within the Department of Pharmaceutical Sciences (DOPS). The MCCF receives funding via CCTSI. Colorado Multiple Institutional Review Board COMIRB# 11-0106.
Publisher Copyright:
© The Author 2016.
PY - 2016/6/13
Y1 - 2016/6/13
N2 - 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 agewas 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.
AB - 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 agewas 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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U2 - 10.1093/jac/dkw005
DO - 10.1093/jac/dkw005
M3 - Article
C2 - 26892777
AN - SCOPUS:84973349104
SN - 0305-7453
VL - 71
SP - 1609
EP - 1618
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
IS - 6
ER -