EVG/COBI/FTC/TAF Bioequivalence Comparing Whole Tablets with Tablets Dissolved in Tap Water.

ABSTRACT

Medication adherence can be challenging for persons with difficulty swallowing tablets. We investigated the bioequivalence of a dissolved tablet when compared with that of a whole tablet of the fixed-dose combination elvitegravir (EVG)/cobicistat (COBI)/emtricitabine (FTC)/tenofovir (TFV) alafenamide fumarate (TAF). A within-subject fixed-order two-period open-label study was conducted in 12 HIV-negative research participants after obtaining informed consent. Participants took a single dose each of the whole tablet and dissolved tablet under direct observation, separated by a 14-day washout period. The dissolved tablet was prepared by adding one whole EVG/COBI/FTC/TAF tablet to 120 mL tap water and stirring. Both dosage types were taken with a standardized meal. Plasma samples were obtained for 72 h postdose. Plasma EVG, FTC, TAF, and TFV were analyzed with liquid chromatographic-tandem mass spectrometric methods. Peak plasma concentration (Cmax) and the area under the concentration-time curve extrapolated to infinity (AUC0-∞) were estimated using WinNonlin software (v.8.3). The primary outcome was bioequivalence consistent with FDA guidance using the 90% confidence interval or the geometric mean ratio. Of 12 participants, 7 were black (58%) and 5 were white (42%), 4 were women (33%), 8 were men (67%), and the mean age was 43.6 years (23-54). There were no complaints about taste with the dissolved tablet. Bioequivalence was established only for FTC. EVG Cmax and AUC0-∞ were higher by 18% and 12%, respectively, when taking the dissolved compared with the whole tablet. TAF AUC0-∞ and Cmax were both 8% lower, whereas TFV Cmax and AUC0-∞ were 8% and 5% lower, respectively, when taken after dissolution. EVG/COBI/FTC/TAF dissolved rapidly in water and had no unpleasant taste. Increases in EVG and decreases in TAF and TFV concentrations were observed when taking dissolved EVG/COBI/FTC/TAF. These changes were judged to be clinically insignificant. Dissolving EVG/COBI/FTC/TAF in water may be suitable for those with pill swallowing challenges. The trial was registered on (//clinicaltrials.gov NCT03717129).