Pharmacokinetics of darunavir/ritonavir and ketoconazole following co-administration in HIV-healthy volunteers

Abstract

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.

Figures

Figure 1

(a) Panel 1. Darunavir plasma profiles following darunavir (DRV) 400 mg bid (▴), and DRV 400 mg bid + ketoconazole (KTZ) 200 mg bid, (♦). (b) Panel 2. Darunavir plasma profiles following DRV/r 400/100 mg bid (•), and DRV/r 400/100 mg bid + KTZ 200 mg bid, (▪)

Figure 2

(a) Panel 1. Ketoconazole plasma profile following darunavir (DRV) 400 mg bid + ketoconazole (KTZ) 200 mg bid, (♦). (b) Panel 2. Ketoconazole plasma profile following KTZ 200 mg bid (•), and DRV/r 400/100 mg bid + KTZ 200 mg bid, (▪)