title: Pharmacokinetics of darunavir in fixed-dose combination with cobicistat compared with coadministration of darunavir and ritonavir as single agents in healthy volunteers.
abstract: This study compared the bioavailability of two candidate fixed-dose combinations (FDCs: G003 and G004) of darunavir/cobicistat 800/150 mg with that of darunavir 800 mg and ritonavir 100 mg coadministered as single agents. Short-term safety and tolerability of the FDC formulations were also assessed. This open-label trial included 36 healthy volunteers and assessed steady-state pharmacokinetics of darunavir over 3 randomized, 10-day treatment sequences, under fed conditions. Blood samples for determination of plasma concentrations of darunavir and cobicistat or ritonavir were taken over 24 hours on day 10 and analyzed by liquid-chromatography tandem mass-spectroscopy. Darunavir AUC24h following administration of the FDCs (G003: 74,780 ng ∙ h/mL and G004: 76,490 ng ∙ h/mL) was comparable to that following darunavir/ritonavir (78,410 ng ∙ h/mL), as was Cmax (6,666 and 6,917 ng/mL versus 6,973 ng/mL, respectively). Modestly lower C0h (1,504 and 1,478 ng/mL versus 2,015 ng/mL) and Cmin (1,167 and 1,224 ng/mL versus 1,540 ng/mL) values were seen with the FDCs. Short-term tolerability of the FDCs was comparable to that of darunavir/ritonavir when administered as single agents. The most common adverse events reported were headache, gastrointestinal upset, or rash. Cobicistat is an effective pharmacoenhancer of darunavir when administered as an FDC. Short-term administration of darunavir/ritonavir or darunavir/cobicistat was generally well tolerated.
authors.affiliation: Janssen Research & Development, LLC, Titusville, NJ, USA.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Kakuda
authors.forename: Magda
authors.initials: M
authors.lastname: Opsomer
authors.forename: Maarten
authors.initials: M
authors.lastname: Timmers
authors.forename: Koen
authors.initials: K
authors.lastname: Iterbeke
authors.forename: Tom
authors.initials: T
authors.lastname: Van De Casteele
authors.forename: Vera
authors.initials: V
authors.lastname: Hillewaert
authors.forename: Romana
authors.initials: R
authors.lastname: Petrovic
authors.forename: Richard M W
authors.initials: RM
authors.lastname: Hoetelmans
mesh_terms: D000328:Adult; D001682:Biological Availability; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000069547:Cobicistat; D018592:Cross-Over Studies; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000069454:Darunavir; D004338:Drug Combinations; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D002219:Carbamates; D065692:Cytochrome P-450 CYP3A Inhibitors; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D013844:Thiazoles; D000069547:Cobicistat; D019438:Ritonavir; D000069454:Darunavir
keywords: bioavailability; cobicistat; darunavir; fixed-dose combination; pharmacoenhancer