Race/Ethnicity and Protease Inhibitor Use Influence Plasma Tenofovir Exposure in Adults Living with HIV-1 in AIDS Clinical Trials Group Study A5202.

Autor: Bednasz CJ; AIDS Clinical Trials Group Pharmacology Specialty Laboratory, New York State Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA amabile@buffalo.edu., Venuto CS; AIDS Clinical Trials Group Pharmacology Specialty Laboratory, New York State Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.; Center for Health + Technology, University of Rochester, Rochester, New York, USA., Ma Q; AIDS Clinical Trials Group Pharmacology Specialty Laboratory, New York State Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA., Daar ES; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and the University of California, Los Angeles, California, USA., Sax PE; Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA., Fischl MA; University of Miami School of Medicine, Miami, Florida, USA., Collier AC; University of Washington School of Medicine and Harborview Medical Center, Seattle, Washington, USA., Smith KY; ViiV Healthcare, Research Triangle Park, North Carolina, USA., Tierney C; Statistical Data Analysis Center, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA., Acosta EP; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama, USA., Mager DE; Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA., Morse GD
Jazyk: angličtina
Zdroj: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2019 Mar 27; Vol. 63 (4). Date of Electronic Publication: 2019 Mar 27 (Print Publication: 2019).
DOI: 10.1128/AAC.01638-18
Abstrakt: AIDS Clinical Trial Group study A5202 (ClinicalTrials.gov identifier NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus either placebo-controlled tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine, in treatment-naive adults living with HIV-1, evaluating efficacy, safety, and tolerability. We report an analysis of the contribution of participant characteristics to the disposition of tenofovir plasma concentrations. Tenofovir concentration data from a total of 817 individuals (88% of the total number of eligible patients randomly assigned to receive treatment in the TDF-containing arms of A5202) were available for analysis. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment models with first-order absorption and first-order elimination were evaluated. An exponential error model was used for examination of interindividual variability (IIV), and a proportional and mixed-error model was assessed for residual variability. The final structural model contained two compartments with first-order absorption and elimination. IIV was estimated for apparent clearance (CL/F) and the first-order absorption rate constant ( k a ), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: k a = 2.87 h -1 , CL/F = 37.2 liters/h, apparent volumes of the central and peripheral compartments = 127 and 646 liters, respectively, and apparent intercompartmental clearance = 107 liters/h. In addition to race/ethnicity, creatinine clearance and assignment to atazanavir/ritonavir or efavirenz were significantly associated with CL/F ( P < 0.001). In conclusion, race/ethnicity is associated with tenofovir oral CL in HIV-1 positive, treatment-naive adults. This covariate relationship raises questions about the possibility of differences in efficacy and risk of adverse events in different patient populations and suggests that examining preexposure prophylaxis regimens and tenofovir exposure in different race/ethnicity groups be considered.
(Copyright © 2019 American Society for Microbiology.)
Databáze: MEDLINE
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