Bioequivalence of the Once‐Daily Single‐Tablet Regimen of Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Compared to Combined Intake of the Separate Agents and the Effect of Food on Bioavailability

Abstract

The effect of food on the bioavailability of the components of the once‐daily, single‐tablet human immunodeficiency virus (HIV) type 1 regimen containing darunavir (DRV 800 mg), cobicistat (COBI 150 mg), emtricitabine (FTC 200 mg), and tenofovir alafenamide (TAF 10 mg) (D/C/F/TAF) (NCT02475135) and the bioequivalence of D/C/F/TAF versus combined intake of the separate agents (NCT02578550) were evaluated. These were 2 phase 1, open‐label, randomized, 2‐period crossover studies (7‐day washout between treatments) in HIV‐negative healthy volunteers. Twenty‐four participants each received a single dose of D/C/F/TAF in fasted conditions (test) or after a standardized high‐fat breakfast (reference). Ninety‐six participants each received a single dose of D/C/F/TAF (test) or combined intake of a single DRV 800‐mg tablet, a COBI 150‐mg tablet, and an FTC/TAF 200/10‐mg tablet (reference), both after a standardized regular‐calorie, regular‐fat breakfast. Pharmacokinetic profiles for all D/C/F/TAF components, safety, and tolerability were assessed. Following D/C/F/TAF in fasted conditions, DRV peak concentration, area under the concentration‐time curve from time of administration until the last time point with a measurable concentration (AUC)last, and extrapolated to infinity (AUCinf) were lower by 45%, 34%, and 30%, respectively, compared with fed conditions, with no clinically relevant differences in COBI, FTC, or TAF exposures between fed and fasted conditions. In the bioequivalence study 90% confidence intervals of the geometric mean ratios of all main pharmacokinetic parameters were within the 80.00% to 125.00% bioequivalence limits for DRV, COBI, FTC, and TAF. No grade 3/4 adverse events (AEs), serious AEs, deaths, or discontinuations due to AEs occurred. D/C/F/TAF is bioequivalent to combined administration of the separate agents. Consistent with other (co)formulations of DRV, DRV exposure was lower in fasted than in fed conditions as evaluated when taken with food, so D/C/F/TAF should be taken with food.

Pharmacokinetics and Bioequivalence Evaluation of 2 Formulations of Tenofovir Alafenamide

“…These findings indicate that food influences the PK parameters of TAF, which is consistent with the previous reports. 16 The reason for the decrease in the value of C max and the increase in the value of AUC 0-t for TAF may be as follows: The gastric emptying rate slows down after eating. Hence, it takes more time for the drugs to reach the small intestine and be absorbed, which delays the t max and lowers the value of C max .…”

Bioequivalence of a Pediatric Fixed‐Dose Combination Tablet Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Compared With Coadministration of the Separate Agents in Healthy Adults: An Open‐Label, Randomized, Replicate Crossover Study

“…Full pharmacokinetic profiles were determined over 72 hours for DRV, COBI, and FTC and over 8 hours for TAF after study drug administration in each treatment period. Plasma samples of DRV, COBI, FTC, and TAF were analyzed using validated liquid chromatography–tandem mass spectrometry methods, as described previously 17 . The pharmacokinetic parameters of interest were C max , area under the plasma concentration–time curve from time zero to last measurable concentration (AUC last ), and area under the plasma concentration–time curve from time zero to infinity (AUC inf ) for DRV, COBI, FTC, and TAF.…”

“…Patients achieved high virologic suppression and low virologic failure rates with D/C/F/TAF over 96 weeks, with no DRV, primary protease inhibitor, or tenofovir resistance–associated mutations observed after baseline 14,16 . In addition, a bioequivalence study showed bioequivalence of the adult D/C/F/TAF 800/150/200/10‐mg FDC relative to the combined administration of the separate commercially available agents DRV, COBI, and FTC/TAF FDC under fed conditions 17 …”

Tenofovir at the Crossroad of the Therapy and Prophylaxis of HIV and HBV Infections

“…A new quadruple drug combination (Symtuza ® ) was launched [11], and an old triple drug combination (Atripla ® ) was not replaced. The advantage of TAF over TDF was that it could be given at a much lower dose (25 mg) as compared to 300 mg for TDF and that, concomitantly, TAF had a much lower risk for nephrotoxicity (tubular nephropathy) and bone toxicity (demineralization).…”