title: Bioequivalence of a darunavir/cobicistat fixed-dose combination tablet versus single agents and food effect in healthy volunteers.
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.
authors: Janssen Research & Development, LLC, Titusville, NJ, USA. tkakuda@its.jnj.com.
authors: Thomas N
authors: TN
authors: Kakuda
authors: Tom
authors: T
authors: Van De Casteele
authors: Romana
authors: R
authors: Petrovic
authors: Mark
authors: M
authors: Neujens
authors: Hiba
authors: H
authors: Salih
authors: Magda
authors: M
authors: Opsomer
authors: Richard Mw
authors: RM
authors: Hoetelmans
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000069547:Cobicistat; D000069454:Darunavir; D004338:Drug Combinations; D016903:Drug Monitoring; D005260:Female; D005502:Food / Q000009:adverse effects; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D013810:Therapeutic Equivalency; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D002219:Carbamates; D004338:Drug Combinations; D013449:Sulfonamides; D013844:Thiazoles; D000069547:Cobicistat; D000069454:Darunavir