Drug Interactions between indinavir and rifabutin

ADJUST DOSE: Coadministration of indinavir and rifabutin may result in increased plasma concentrations of rifabutin and decreased plasma concentrations of indinavir. The mechanism involves indinavir inhibition of rifabutin metabolism via CYP450 3A4 and, conversely, rifabutin induction of indinavir metabolism via the same isoenzyme. Indinavir at a dosage of 800 mg every 8 hours has been shown to increase rifabutin systemic exposure (AUC) by 204% compared to rifabutin given alone at 300 mg daily, and the combination has been associated with uveitis secondary to rifabutin toxicity. Subsequently, it was demonstrated in 17 healthy volunteers that the currently recommended adjusted dosages of indinavir (1000 mg every 8 hours) and rifabutin (150 mg once a day) given together for 14 days produced mean AUC values of rifabutin and its pharmacologically active metabolite that were still 70% and 120% higher, respectively, than with 300 mg rifabutin daily alone. The clinical significance of these increases is unknown. Rifabutin given either at 150 mg or 300 mg daily has been shown to decrease indinavir AUC by approximately 30%. In 11 HIV-infected subjects, the recommended adjusted dosages appeared to compensate for rifabutin induction of indinavir metabolism, as the pharmacokinetic profile of adjusted indinavir with rifabutin was nearly identical to that of indinavir given at the standard dosage alone.

MANAGEMENT: To minimize the risk of rifabutin toxicity including leukopenia, uveitis, arthralgias and skin discoloration, indinavir labeling recommends that rifabutin be administered at half the standard dosage in patients treated with indinavir. Some experts suggest decreasing rifabutin dose from 300 to 150 mg if given daily but administering the full 300 mg dose during intermittent therapy (i.e., twice- or three-times-weekly directly observed therapy). Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, indinavir labeling and some experts also recommend increasing the dosage of indinavir to 1000 mg three times a day during coadministration with rifabutin.