生物学的同等性とバイオアベイラビリティのジャーナル

概要

Bioequivalence of Two Co-formulations of Emtricitabine/Tenofovir Alafenamide Fixed-Dose Combinations with 200/10 mg and 200/25 mg

Zack J, Chu H, Chuck S, Rhee M, Koziara J, West S, Fang L and Kearney B

Emtricitabine/tenofovir alafenamide (FTC/TAF) is the next advancement in nucleotide reverse transcriptase inhibitor (NRTI) backbone for the treatment of HIV-1 in adults. Tenofovir disoproxil fumarate (TDF), an oral prodrug of tenofovir (TFV), is a preferred NRTI, but it is also associated with nephrotoxicity and reduced bone mineral density (BMD). TDF has been replaced by TAF, a novel, prodrug of TFV with a unique metabolic pathway leading to >90% lower circulating plasma of TFV. Less nephrotoxicity, less BMD reduction in treatment-naïve subjects, and BMD increase in virologically suppressed patients on TAF in clinical trials. The two studies presented here were conducted in healthy subjects. Study 1472 evaluated the pharmacokinetics (PK) and bioequivalence (BE) of the components of FTC/TAF 200/10 mg fixed-dose combination (FDC) administered with elvitegravir 150 mg and cobicistat 150 mg tablets to elvitegravir (E)/cobicistat (C)/FTC (F)/TAF (150/150/200/10 mg) single-tablet regimen (STR). Study 1473 evaluated the PK and BE of the components of FTC/TAF 200/25 FDC to E/C/F/TAF STR. One-hundred and 116 subjects were randomized into the single-dose, open-label, 2-way, crossover Phase 1 Study 1472 and Study 1473, respectively; two subjects did not complete Study 1472. Serial blood samples were obtained over 144 hours after 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 FTC/TAF FDC to FTC and TAF administered as E/C/F/ TAF STR. The test and reference treatments 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 and TAF. FTC/TAF 200/10 mg and 200/25 mg are the next advancement in NRTI backbone for treatment of HIV-1 adults and adolescents, with an emphasis on safety while maintaining the efficacy and convenience of its predecessor.