Article date: August 2008
By: Vanitha J. Sekar, Eric Lefebvre, Martine De Pauw, Tony Vangeneugden, Richard M. Hoetelmans, in Volume 66, Issue 2, pages 215-221
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
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 (AUC12h), maximum plasma concentration (Cmax) and minimum plasma concentration (Cmin) increased by 155% (80, 261), 78% (28, 147) and 179% (58, 393), respectively, compared with treatment with darunavir alone. Darunavir AUC12h, Cmax and Cmin 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 AUC12h, Cmax and Cmin 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.
DOI: 10.1111/j.1365-2125.2008.03191.x
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