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Pharmacokinetics of darunavir/ritonavir and ketoconazole following co‐administration in HIV–healthy volunteers
Author(s) -
Sekar Vanitha J.,
Lefebvre Eric,
De Pauw Martine,
Vangeneugden Tony,
Hoetelmans Richard M.
Publication year - 2008
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2008.03191.x
Subject(s) - darunavir , ketoconazole , ritonavir , pharmacology , pharmacokinetics , medicine , drug interaction , tolerability , cyp3a4 , adverse effect , human immunodeficiency virus (hiv) , cytochrome p450 , immunology , viral load , antifungal , dermatology , antiretroviral therapy , metabolism
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme system. • Co‐administration of ketoconazole and drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentrations of the drugs, which could increase or prolong both therapeutic and adverse effects. • Therefore, unless otherwise specified, appropriate dosage adjustments may be necessary. WHAT THIS PAPER ADDS • The current study was conducted to determine the extent of interaction between the potent CYP3A inhibitor, ketoconazole, and the CYP 3A substrate, darunavir (given alone and with low‐dose ritonavir). • This information provides data on the pharmacokinetic boosting ability of ketoconazole and serves as important guidance to HIV‐infected patients and their treating physicians with regard to appropriate (co‐)administration of darunavir/ritonavir and ketoconazole. Aims To investigate the interaction between ketoconazole and darunavir (alone and in combination with low‐dose ritonavir), in HIV–healthy volunteers. Methods Volunteers received darunavir 400 mg bid and darunavir 400 mg bid plus ketoconazole 200 mg bid, in two sessions (Panel 1), or darunavir/ritonavir 400/100 mg bid, ketoconazole 200 mg bid and darunavir/ritonavir 400/100 mg bid plus ketoconazole 200 mg bid, over three sessions (Panel 2). Treatments were administered with food for 6 days. Steady‐state pharmacokinetics following the morning dose on day 7 were compared between treatments. Short‐term safety and tolerability were assessed. Results Based on least square means ratios (90% confidence intervals) , during darunavir and ketoconazole co‐administration, darunavir area under the curve (AUC 12h ), maximum plasma concentration ( C max ) and minimum plasma concentration ( C min ) increased by 155% (80, 261), 78% (28, 147) and 179% (58, 393), respectively, compared with treatment with darunavir alone. Darunavir AUC 12h , C max and C min increased by 42% (23, 65), 21% (4, 40) and 73% (39, 114), respectively, during darunavir/ritonavir and ketoconazole co‐administration, relative to darunavir/ritonavir treatment. Ketoconazole pharmacokinetics was unchanged by co‐administration with darunavir alone. Ketoconazole AUC 12h , C max and C min increased by 212% (165, 268), 111% (81, 144) and 868% (544, 1355), respectively, during co‐administration with darunavir/ritonavir compared with ketoconazole alone. Conclusions The increase in darunavir exposure by ketoconazole was lower than that observed previously with ritonavir. A maximum ketoconazole dose of 200 mg day −1 is recommended if used concomitantly with darunavir/ritonavir, with no dose adjustments for darunavir/ritonavir.