1. Race/Ethnicity and Protease Inhibitor Use Influence Plasma Tenofovir Exposure in Adults Living with HIV-1 in AIDS Clinical Trials Group Study A5202
- Author
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Cindy J. Bednasz, Charles S. Venuto, Qing Ma, Eric S. Daar, Paul E. Sax, Margaret A. Fischl, Ann C. Collier, Kimberly Y. Smith, Camlin Tierney, Edward P. Acosta, Donald E. Mager, Gene D. Morse, Hector H. Bolivar, Sandra Navarro, Susan L. Koletar, Diane Gochnour, Edward Seefried, Julie Hoffman, Judith Feinberg, Michelle Saemann, Kristine Patterson, Donna Pittard, David Currin, Kerry Upton, Michael Saag, Graham Ray, Steven Johnson, Bartolo Santos, Connie A. Funk, Michael Morgan, Brenda Jackson, Pablo Tebas, Aleshia Thomas, Ge-Youl Kim, Michael K. Klebert, Jorge L. Santana, Santiago Marrero, Jane Norris, Sandra Valle, Gary Matthew Cox, Martha Silberman, Sadia Shaik, Ruben Lopez, Margie Vasquez, Demetre Daskalakis, Christina Megill, Todd Stroberg, Jessica Shore, Babafemi Taiwo, Mitchell Goldman, Molly Boston, Jeffrey Lennox, Carlos del Rio, Timothy W. Lane, Kim Epperson, Annie Luetkemeyer, Mary Payne, Barbara Gripshover, Dawn Antosh, Jane Reid, Mary Adams, Sheryl S. Storey, Shelia B. Dunaway, Joel Gallant, Ilene Wiggins, Joan A. Swiatek, Joseph Timpone, Princy Kumar, Ardis Moe, Maria Palmer, Jon Gothing, Joanne Delaney, Kim Whitely, Ann Marie Anderson, Scott M. Hammer, Michael T. Yin, Mamta Jain, Tianna Petersen, Roberto Corales, Christine Hurley, Keith Henry, Bette Bordenave, Amanda Youmans, Mary Albrecht, Richard B. Pollard, Abimbola Olusanya, Paul R. Skolnik, Betsy Adams, Karen T. Tashima, Helen Patterson, Michelle Ukwu, Lauren Rogers, Henry H. Balfour, Kathy A. Fox, Susan Swindells, Frances Van Meter, Gregory Robbins, Nicole Burgett-Yandow, Charles E. Davis, Colleen Boyce, William A. O’Brien, Gerianne Casey, Chiu-Bin Hsaio, Jeffrey L. Meier, Jack T. Stapleton, Donna Mildvan, Manuel Revuelta, Wafaa El Sadr, Avelino Loquere, Nyef El-Daher, Tina Johnson, Robert Gross, Kathyrn Maffei, Valery Hughes, Glenn Sturge, Deborah McMahon, Barbara Rutecki, Michael Wulfsohn, Andrew Cheng, Norbert Bischofberger, Lynn Dix, and Qiming Liao
- Subjects
Adult ,Cyclopropanes ,Male ,medicine.medical_specialty ,Efavirenz ,Anti-HIV Agents ,Renal function ,HIV Infections ,Emtricitabine ,Models, Biological ,030226 pharmacology & pharmacy ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Abacavir ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Tenofovir ,Pharmacology ,0303 health sciences ,Ritonavir ,030306 microbiology ,business.industry ,virus diseases ,Lamivudine ,HIV Protease Inhibitors ,Middle Aged ,Dideoxynucleosides ,Benzoxazines ,Atazanavir ,Drug Combinations ,Infectious Diseases ,Tolerability ,chemistry ,Alkynes ,HIV-1 ,Female ,business ,medicine.drug - Abstract
AIDS Clinical Trial Group study A5202 (ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00118898","term_id":"NCT00118898"}}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.
- Published
- 2019