Author:
Bednasz Cindy J.,Venuto Charles S.,Ma Qing,Daar Eric S.,Sax Paul E.,Fischl Margaret A.,Collier Ann C.,Smith Kimberly Y.,Tierney Camlin,Acosta Edward P.,Mager Donald E.,Morse Gene D.,Bolivar Hector H.,Navarro Sandra,Koletar Susan L.,Gochnour Diane,Seefried Edward,Hoffman Julie,Feinberg Judith,Saemann Michelle,Patterson Kristine,Pittard Donna,Currin David,Upton Kerry,Saag Michael,Ray Graham,Johnson Steven,Santos Bartolo,Funk Connie A.,Morgan Michael,Jackson Brenda,Tebas Pablo,Thomas Aleshia,Kim Ge-Youl,Klebert Michael K.,Santana Jorge L.,Marrero Santiago,Norris Jane,Valle Sandra,Cox Gary Matthew,Silberman Martha,Shaik Sadia,Lopez Ruben,Vasquez Margie,Daskalakis Demetre,Megill Christina,Stroberg Todd,Shore Jessica,Taiwo Babafemi,Goldman Mitchell,Boston Molly,Lennox Jeffrey,del Rio Carlos,Lane Timothy W.,Epperson Kim,Luetkemeyer Annie,Payne Mary,Gripshover Barbara,Antosh Dawn,Reid Jane,Adams Mary,Storey Sheryl S.,Dunaway Shelia B.,Gallant Joel,Wiggins Ilene,Smith Kimberly Y.,Swiatek Joan A.,Timpone Joseph,Kumar Princy,Moe Ardis,Palmer Maria,Gothing Jon,Delaney Joanne,Whitely Kim,Anderson Ann Marie,Hammer Scott M.,Yin Michael T.,Jain Mamta,Petersen Tianna,Corales Roberto,Hurley Christine,Henry Keith,Bordenave Bette,Youmans Amanda,Albrecht Mary,Pollard Richard B.,Olusanya Abimbola,Skolnik Paul R.,Adams Betsy,Tashima Karen T.,Patterson Helen,Ukwu Michelle,Rogers Lauren,Balfour Henry H.,Fox Kathy A.,Swindells Susan,Van Meter Frances,Robbins Gregory,Burgett-Yandow Nicole,Davis Charles E.,Boyce Colleen,O’Brien William A.,Casey Gerianne,Morse Gene D.,Hsaio Chiu-Bin,Meier Jeffrey L.,Stapleton Jack T.,Mildvan Donna,Revuelta Manuel,Currin David,El Sadr Wafaa,Loquere Avelino,El-Daher Nyef,Johnson Tina,Gross Robert,Maffei Kathyrn,Hughes Valery,Sturge Glenn,McMahon Deborah,Rutecki Barbara,Wulfsohn Michael,Cheng Andrew,Bischofberger Norbert,Dix Lynn,Liao Qiming
Abstract
ABSTRACT
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 (ka), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: ka = 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.
Funder
University of Washington Center for AIDS Research
University of Rochester Center for AIDS Research
University of North Carolina Center for AIDS Research
University at Buffalo and University of Alabama Pharmacology Specialty Laboratory
HHS | NIH | National Institute of Allergy and Infectious Diseases
HHS | NIH | National Institute of Mental Health
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology