Rifabutin is an inducer and substrate of CYP3A. An increase of systemic exposure to darunavir was observed when darunavir coadministered with 100 mg ritonavir was coadministered with rifabutin 150 mg (once every other day). Darunavir AUC, Cmax and Cmin increased by 53%, 39% and 68%, respectively. Based on the sum of the active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite), rifabutin AUC increased by 55% and there was no significant change in Cmax. The interaction trial showed a comparable daily systemic exposure for rifabutin between treatment at 300 mg (once daily) alone and 150 mg (once every other day) in combination with darunavir/ritonavir (600/100 mg twice daily) with an about 10-fold increase in the daily exposure to the active metabolite 25-O-desacetylrifabutin. Furthermore, AUC of the sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite) was increased 1.6-fold, while Cmax remained comparable. Data on comparison with a 150 mg (once daily) reference dose is lacking. A dosage reduction of rifabutin by 75% of the usual dose of 300 mg/day (i.e. rifabutin 150 mg once every other day) and increased monitoring for rifabutin related adverse events is warranted in patients receiving the combination with darunavir co-administered with ritonavir. In case of safety issues, a further increase of the dosing interval for rifabutin and/or monitoring of rifabutin levels should be considered. Consideration should be given to official guidance on the appropriate treatment of tuberculosis in HIV infected patients. Based upon the safety profile of darunavir/ritonavir, the increase in darunavir exposure in the presence of rifabutin does not warrant a dose adjustment for darunavir/ritonavir. Based on pharmacokinetic modeling, this dosage reduction of 75% is also applicable if patients receive rifabutin at doses other than 300 mg/day.

Coadministration of rifabutin (150 mg every other day) and darunavir/ritonavir (600/100 mg twice daily) was studied in 11 subjects. The AUC, Cmax and Cmin of darunavir increased by 57%, 42% and 75%, respectively. When compared to rifabutin 300 mg once daily alone, rifabutin AUC and Cmax decreased by 7% and 28%, but Cmin increased by 64%. The AUC, Cmax and Cmin of 25-O-desactyl rifabutin increased by 9.81-fold, 4.77-fold and 27.1-fold, respectively. Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary. 

Coadministration of darunavir/ritonavir (600/100 mg twice daily) and rifabutin (300 mg once daily alone or 150 mg every other day when coadministered) was studied in HIV- subjects. Rifabutin AUC was comparable when given at the standard dose alone or at the reduced dose in combination. The AUC of 25-O-desacetyl rifabutin increased by 9.8-fold when coadministered with darunavir/ritonavir. Coadministration increased the AUC of darunavir by 57% and increased ritonavir AUC by 66%. Adverse events were more common with combined treatment and 18/27 subjects discontinued prematurely. A dose reduction of rifabutin by 75% (i.e., 150 mg every other day) and increased monitoring for rifabutin-related adverse events is warranted when coadministered with darunavir/ritonavir.