Drug Interactions between atazanavir / cobicistat and rifabutin

GENERALLY AVOID: Coadministration with cobicistat may significantly increase the plasma concentrations of rifabutin and its metabolite, 25-O-desacetylrifabutin. The proposed mechanism is cobicistat inhibition of rifabutin metabolism via CYP450 3A4. In 12 healthy volunteers, administration of rifabutin 150 mg once every other day in combination with 150 mg once daily each of cobicistat and elvitegravir had no significant effect on the pharmacokinetics of rifabutin, but increased mean 25-O-desacetyl-rifabutin peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by approximately 4.8-, 6.3- and 4.9-fold, respectively, compared to administration of rifabutin alone at 300 mg once daily. Uveitis and neutropenia secondary to rifabutin toxicity may occur. On the other hand, cobicistat plasma concentrations may be significantly decreased due to CYP450 3A4 induction by rifabutin. In the same study mentioned above, the Cmin of cobicistat decreased by 66%.

MANAGEMENT: Concomitant use of cobicistat-containing fixed combination antiretroviral products with rifabutin is not recommended. However, if concomitant use is needed, to minimize the risk of rifabutin toxicity including leucopenia, uveitis, arthralgias, and skin discoloration, some authorities recommend that the rifabutin dosage be reduced to 150 mg every other day or three times a week in patients treated with cobicistat. A further dosage reduction of rifabutin to 150 mg twice weekly may be necessary for patients in whom the 150 mg three times per week dose is not tolerated. A complete blood count should be performed at least weekly and as clinically indicated to monitor for development of neutropenia. Due to the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, close monitoring of antiretroviral response is also recommended. Current guidelines should be consulted for the appropriate treatment of tuberculosis in HIV-infected patients.

ADJUST DOSE: Coadministration with atazanavir may significantly increase the plasma concentrations of rifabutin and its active 25-O-desacetyl metabolite. The mechanism is atazanavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of rifabutin. In 3 study subjects, atazanavir (600 mg once a day for 10 days) increased the mean steady-state peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and trough plasma concentration (Cmin) of rifabutin (300 mg once daily for 10 days followed by 150 mg once a day for 10 days) by 18%, 110% and 243%, respectively. The Cmax, AUC and Cmin of the 25-O-desacetyl metabolite were 8, 22, and 75 times the values observed with rifabutin alone. In another study, 7 subjects administered atazanavir/ritonavir (300 mg/100 mg once daily for 17 days) also increased Cmax, AUC and Cmin of rifabutin (150 mg twice weekly for 15 days) by 149%, 48% and 40%, respectively.

MANAGEMENT: Use of atazanavir-cobicistat with rifabutin is considered contraindicated by some authorities (Australia). However, if concomitant use of atazanavir-cobicistat, or atazanavir-ritonavir with rifabutin is needed, some authorities recommend a reduction in the rifabutin dosage of up to 75% (e.g., 150 mg every other day or three times per week). A further dosage reduction of rifabutin to 150 mg twice weekly may be necessary for patients in whom the 150 mg three times per week dose is not tolerated. Patients should be monitored for rifabutin toxicity such as leucopenia, uveitis, arthralgias and skin discoloration. Current guidelines should be consulted for the appropriate treatment of tuberculosis in HIV infected patients.