Drug Interactions between nelfinavir and rifabutin

ADJUST DOSE: Coadministration of nelfinavir and rifabutin may result in increased plasma concentrations of rifabutin and decreased plasma concentrations of nelfinavir. The mechanism involves nelfinavir inhibition of rifabutin metabolism via CYP450 3A4 and, conversely, rifabutin induction of nelfinavir metabolism via the same isoenzyme. Nelfinavir at a dosage of 750 mg every 8 hours has been shown to increase the steady-state peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and trough plasma concentration (Cmin) of rifabutin in 10 study subjects by 146%, 207% and 305%, respectively, compared to rifabutin given alone at 300 mg daily. This dosage of rifabutin in combination with other protease inhibitors has been associated with uveitis secondary to rifabutin toxicity. Subsequently, it was demonstrated in 12 study subjects that even after reducing rifabutin dosage to 150 mg once a day as commonly recommended when used in combination with nelfinavir, mean rifabutin AUC and Cmin were still 83% and 177% higher, respectively, than with 300 mg rifabutin daily alone. The clinical significance of these increases is unknown. Rifabutin 300 mg daily decreased nelfinavir Cmax, AUC and Cmin by 24%, 32% and 53%, respectively, while rifabutin 150 mg daily decreased the same values by 18%, 23% and 25%. No significant effects of rifabutin were observed when nelfinavir was given as 1250 mg twice a day.

MANAGEMENT: To minimize the risk of rifabutin toxicity including leukopenia, uveitis, arthralgias and skin discoloration, nelfinavir labeling recommends that rifabutin be administered at half the standard dosage in patients treated with nelfinavir. 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, nelfinavir labeling also recommends using the 1250 mg twice a day dosage during coadministration with rifabutin. Alternatively, some experts recommend increasing the dose of nelfinavir from 750 to 1000 mg if the three-times-a-day dosing is used.

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