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

Introduction AIDS Clinical Trial Group 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-naïve adults living with HIV-1, evaluating efficacy, safety and tolerability. We report an analysis on the contribution of participant characteristics to the disposition of tenofovir plasma concentrations.

Methods Tenofovir concentration data from a total of 817 individuals (88%) 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 inter-individual variability (IIV), and a proportional and mixed error model was assessed for residual variability.

Results 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. Final mean parameter estimates were: ka = 2.87 hr^-1, CL/F = 37.2 L/hr, apparent volumes of the central and peripheral compartments = 127 and 646 L, and apparent inter-compartmental clearance = 107 L/h. In addition to race/ethnicity, creatinine clearance and assignment to atazanavir/r or efavirenz were significantly associated with CL/F (p < 0.001).

Conclusion Race/ethnicity is associated with tenofovir oral CL in HIV-1 positive, treatment-naïve 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 pre-exposure prophylaxis regimens and TFV exposure in different race/ethnicity groups be considered.

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