Journal of Bioequivalence & Bioavailability

Abstract

Bioequivalence of the Rilpivirine/Emtricitabine/Tenofovir Alafenamide Single-Tablet Regimen

Zack J, Chuck S, Chu H, Graham H, Cao H, Tijerina M, West S, Fang L, Quirk E and Kearney B

Rilpivirine/emtricitabine/tenofovir alafenamide (RPV/FTC/TAF) is the next advancement in once-daily antiretroviral single-tablet regimen (STR) for the treatment of HIV-1 in adults. Tenofovir disoproxil fumarate (TDF), an oral prodrug of tenofovir (TFV), is a preferred nucleotide reverse transcriptase inhibitor, but it is also associated with nephrotoxicity and reduced bone mineral density (BMD). TDF has been replaced by tenofovir alafenamide (TAF), a novel, oral prodrug of TFV with a different metabolic pathway leading to 91% lower circulating plasma concentrations of TFV. Differences with TAF have resulted in less nephrotoxicity and less reduction or increase in BMD in clinical trials. This study evaluated the pharmacokinetics and bioequivalence of the components of RPV/FTC/TAF (25/200/25 mg) STR to the references of RPV (25 mg) single tablet and elvitegravir (E)/cobicistat (C)/FTC (F)/TAF (150/150/200/10 mg) in healthy subjects. Ninety-six subjects were randomized in a single-dose, open-label, 3-way, 6-sequence, crossover Phase 1 study; two subjects did not complete the study. Serial blood samples were obtained over 336 hours for RPV/FTC/ TAF and RPV and over 144 hours for E/C/F/TAF following oral administration of each treatment, and pharmacokinetic parameters were calculated. Formulation bioequivalence was assessed by 90% confidence intervals (CIs) for the geometric least-squares mean (GLSM) ratios of pharmacokinetic parameter AUClast, AUCinf, and Cmax for each component of RPV/FTC/TAF compared to RPV and E/C/F/TAF. The test and reference treatments administered under fed conditions were generally well tolerated. The 90% CIs for the GLSM ratios of the primary pharmacokinetic parameter AUClast, AUCinf, and Cmax for test versus reference treatments were within the protocol-specified bioequivalence boundary of 80% to 125% for FTC, RPV, and TAF. RPV/FTC/TAF is the next advancement in once-daily STR for the treatment of HIV-1 in adults. Once approved, it will add to the armamentarium of STRs available for efficacious and safe therapies.