Bioequivalence of a Darunavir/Cobicistat Fixed-Dose Combination Tablet versus Single Agents and Food Effect in Healthy Volunteers. Issue 6 (August 2014)

• Record Type: Journal Article
• Authors: Kakuda, Thomas N; Van De Casteele, Tom; Petrovic, Romana; Neujens, Mark; Salih, Hiba; Opsomer, Magda; Hoetelmans, Richard MW
• Is Part Of: Antiviral therapy. Volume 19:Issue 6(2014)
• Page Start: 597
• Page End: 606
• Publication Date: 2014-08
• Subjects: Antiviral agents -- Periodicals; Antiviral Agents -- therapeutic use; Virus Diseases -- therapy; Viruses -- drug effects; Antiviral agents; Periodical; Electronic journals; Periodicals; 616.9106
• DOI: 10.3851/IMP2814
• Languages: English
• ISSNs: 1359-6535

Abstract

Background: Darunavir requires pharmacokinetic enhancement to increase its bioavailability. Cobicistat is potentially an alternative pharmacokinetic booster to ritonavir. Bioequivalence of a darunavir/cobicistat fixed-dose combination (FDC) versus darunavir and cobicistat co-administered as single agents and the effect of a high-fat meal on the pharmacokinetics of the FDC were evaluated. Methods: In this Phase I, open-label, randomized, three-panel, crossover study (NCT01619527), healthy volunteers received a single dose of darunavir (800 mg) with cobicistat (150 mg) as either an FDC or as single agents co-administered under fasted (panel 1, n =74) or fed (breakfast, panel 2, n =40) conditions, or as the FDC under fasted versus fed (high-fat breakfast) conditions (panel 3, n =19), with a ≥7 day washout period between treatments. Pharmacokinetic profiles, safety and tolerability were assessed. Results: 90% confidence intervals of the least square mean ratios for darunavir and cobicistat maximum plasma concentration and area under the plasma concentration–time curve (AUC) were all within 80.00% and 125.00% in panels 1 and 2. Administration of the FDC with a high-fat breakfast significantly increased darunavir maximum plasma concentration 2.27-fold and AUC 1.63–1.70-fold, whereas cobicistat pharmacokinetics were unaffected. No volunteers discontinued due to adverse events (AEs). All AEs were grade 1 or 2. Overall, 27 (20%) and 26 (20%) volunteers had ≥1 AE at least possibly related to darunavir and cobicistat, respectively. Conclusions: Bioequivalence of the darunavir/cobicistat 800/150-mg FDC was demonstrated versus darunavir and cobicistat co-administered as single agents under fasted or fed conditions. Food increased darunavir exposure, therefore, darunavir/cobicistat should be administered with food.