Pharmacokinetics of darunavir/ritonavir and rifabutin coadministered in HIV-negative healthy volunteers.
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Study Design
The drug-drug interaction between rifabutin (RFB) and darunavir/ritonavir (DRV/r) was examined in a randomized, three-way crossover study of HIV-negative healthy volunteers who received DRV/r 600/100 mg twice a day (BID) (treatment A), RFB 300 mg once a day (QD) (treatment B), and DRV/r 600/100 mg BID plus RFB 150 mg every other day (QOD) (treatment C). The sequence of treatments was randomized, and each treatment period lasted 12 days. Full pharmacokinetic profiles were determined for DRV, ritonavir, and RFB and its active metabolite, 25-O-desacetylrifabutin (desRFB), on day 13.
Study Results
The DRV and ritonavir areas under the plasma concentration-time curve from zero to 12 h (AUC12h) increased by 57% and 66%, respectively, in the presence of RFB. The RFB exposure was comparable between treatment with RFB QD alone (treatment B) and treatment with DRV/r plus RFB QOD (treatment C); however, based on least-square means ratios, the minimum plasma concentration (Cmin) increased by 64% and the maximum plasma concentration (Cmax) decreased by 28%, respectively. The exposure (AUC within the dosage interval and at steady state [AUCτ]) to desRFB was considerably increased (by 881%) following treatment with DRV/r/RFB. The exposure to the parent drug plus the metabolite increased 1.6-fold in the presence of DRV/r. Adverse events (AEs) were more commonly reported during combined treatment (83% versus 44% for RFB and 28% for DRV/r); similarly, grade 3-4 AEs occurred in 17% versus 11% and 0%, respectively, of volunteers. Eighteen of 27 volunteers (66.7%) prematurely discontinued the trial; all volunteers discontinuing for safety reasons (n = 9) did so during RFB treatment phases. These results suggest that DRV/r may be coadministered with RFB with a dose adjustment of RFB to 150 mg QOD and increased monitoring for RFB-related AEs.
Study Conclusions
Based on the overall safety profile of DRV/r, no dose adjustment of DRV/r is considered to be warranted. The US guidelines for HIV treatment now recommend the administration of rifabutin at a daily dosage of 150 mg with a boosted protease inhibitor. Due to the limited safety data with this dose and combination, patients receiving rifabutin 150 mg daily with a boosted protease inhibitor should be closely monitored for rifabutin-related toxicities. Based upon the safety profile of darunavir/ritonavir, the increase in darunavir exposure does not warrant a dose adjustment for darunavir/ritonavir.
References
Sekar V, Lavreys L, Van de Casteele T, Berckmans C, Spinosa-Guzman S, Vangeneugden T, Hoetelmans R. Pharmacokinetics of darunavir/ritonavir and rifabutin coadministered in hiv-negative healthy volunteers. Journal Of Antimicrobial Agents And Chemotherapy. 2010; 10: 4440-4445.
Pharmacokinetics of darunavir/ritonavir and rifabutin coadministered in HIV-negative healthy volunteers.
^
Study Design
The drug-drug interaction between rifabutin (RFB) and darunavir/ritonavir (DRV/r) was examined in a randomized, three-way crossover study of HIV-negative healthy volunteers who received DRV/r 600/100 mg twice a day (BID) (treatment A), RFB 300 mg once a day (QD) (treatment B), and DRV/r 600/100 mg BID plus RFB 150 mg every other day (QOD) (treatment C). The sequence of treatments was randomized, and each treatment period lasted 12 days. Full pharmacokinetic profiles were determined for DRV, ritonavir, and RFB and its active metabolite, 25-O-desacetylrifabutin (desRFB), on day 13.
Study Results
The DRV and ritonavir areas under the plasma concentration-time curve from zero to 12 h (AUC12h) increased by 57% and 66%, respectively, in the presence of RFB. The RFB exposure was comparable between treatment with RFB QD alone (treatment B) and treatment with DRV/r plus RFB QOD (treatment C); however, based on least-square means ratios, the minimum plasma concentration (Cmin) increased by 64% and the maximum plasma concentration (Cmax) decreased by 28%, respectively. The exposure (AUC within the dosage interval and at steady state [AUCτ]) to desRFB was considerably increased (by 881%) following treatment with DRV/r/RFB. The exposure to the parent drug plus the metabolite increased 1.6-fold in the presence of DRV/r. Adverse events (AEs) were more commonly reported during combined treatment (83% versus 44% for RFB and 28% for DRV/r); similarly, grade 3-4 AEs occurred in 17% versus 11% and 0%, respectively, of volunteers. Eighteen of 27 volunteers (66.7%) prematurely discontinued the trial; all volunteers discontinuing for safety reasons (n = 9) did so during RFB treatment phases. These results suggest that DRV/r may be coadministered with RFB with a dose adjustment of RFB to 150 mg QOD and increased monitoring for RFB-related AEs.
Study Conclusions
Based on the overall safety profile of DRV/r, no dose adjustment of DRV/r is considered to be warranted. The US guidelines for HIV treatment now recommend the administration of rifabutin at a daily dosage of 150 mg with a boosted protease inhibitor. Due to the limited safety data with this dose and combination, patients receiving rifabutin 150 mg daily with a boosted protease inhibitor should be closely monitored for rifabutin-related toxicities. Based upon the safety profile of darunavir/ritonavir, the increase in darunavir exposure does not warrant a dose adjustment for darunavir/ritonavir.
References
Sekar V, Lavreys L, Van de Casteele T, Berckmans C, Spinosa-Guzman S, Vangeneugden T, Hoetelmans R. Pharmacokinetics of darunavir/ritonavir and rifabutin coadministered in hiv-negative healthy volunteers. Antimicrobial Agents And Chemotherapy. 2010; 10: 4440-4445.
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