Pharmacokinetics and Bioavailability of an Integrase and Novel Pharmacoenhancer-Containing Single-Tablet Fixed-Dose Combination Regimen for the Treatment of HIV

Objective: This study evaluated the relative bioavailability and pharmacokinetics of elvitegravir (EVG), emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), and a investigational pharmacoenhancer, cobicistat (GS-9350, COBI) coformulated as a fixed-dose combination tablet (FDC) compared with ritonavir-boosted EVG and FTC + TDF in healthy subjects. Methods: Subjects were randomized to 1 of 2 sequences. All treatments were administered in the morning for 10 days with food, separated by a 2-day washout. Blood samples were collected over 24 hours with the last dose of each treatment. Results: Forty-four subjects enrolled, 42 subjects completed all periods. All study treatments were generally well tolerated. Relative to ritonavir-boosted EVG, the geometric least-squares means ratios (GMR) [90% confidence interval (CI)] for EVG area under plasma concentration-time curve from time zero until the end of the dosing interval (AUC)(tau), maximum concentration (C(max)), and trough concentration (C(tau)) were 118 (110 to 126), 108 (100 to 116), and 110 (95.3 to 127), respectively, with EVG/COBI 150 mg/FTC/TDF. Relative to FTC + TDF, FTC GMR, and 90% CI were 127 (115 to 140) for AUC(tau), 121 (107 to 137) for C(max), and 126 (118 to 136) for C(tau); tenofovir (TFV) GMR and 90% CI were 118 (114 to 122), 130 (122 to 138), and 124 (119 to 129) for AUC(tau), C(max), and C(tau), respectively, with EVG/COBI 150 mg/FTC/TDF. Conclusions: Fixed-dose combination tablet containing COBI 150 mg resulted in desired high EVG C(tau) concentrations and clinically equivalent tenofovir and FTC exposures relative to currently approved individual agents and was thus selected for subsequent evaluation.