Drug Interactions between rifabutin and saquinavir

ADJUST DOSE: Coadministration with rifabutin may decrease the plasma concentrations of saquinavir. The mechanism is rifabutin induction of saquinavir metabolism via CYP450 3A4. According to the product labeling, coadministration of saquinavir mesylate (hard gelatin capsule, or HGC, 600 mg three times a day) with rifabutin (300 mg once a day) for 14 days resulted in a 30% decrease in steady-state saquinavir peak plasma concentration (Cmax) and a 43% decrease in systemic exposure (AUC) in a group of 12 HIV-infected subjects. Similarly, in a study of 14 HIV-infected patients, rifabutin (300 mg once a day for 10 days) decreased the mean steady-state Cmax and AUC of saquinavir (soft gelatin capsule, or SGC, 1200 mg three times a day for 10 days) by 39% and 47%, respectively, compared to administration of saquinavir alone. Steady-state rifabutin Cmax and AUC increased by an average of approximately 45% each. In another study, coadministration of saquinavir mesylate/ritonavir (HGC 400 mg/400 mg twice a day) with rifabutin (150 mg every 3 days or 300 mg every 7 days) in 24 patients resulted in a 39% increase in saquinavir Cmax and a 19% increase in AUC, which are not considered clinically significant. In addition, when compared to a rifabutin 150 mg once daily dose, administration of rifabutin 150 mg every four days with saquinavir mesylate/ritonavir (1000 mg/100 mg twice a day) in 11 healthy volunteers did not affect the systemic exposure over 96 hours (AUC (0-96)) of rifabutin but increased the Cmax by 68%; however, the AUC (0-96) and Cmax of the rifabutin active moiety (sum of rifabutin and 25-O-desacetyl rifabutin) by 60% and 111%, respectively. The saquinavir and ritonavir levels were not significantly affected.

MANAGEMENT: No dose adjustment of saquinavir/ritonavir (1000 mg/100 mg twice a day) is recommended if used in combination with rifabutin. However, it is recommended that the dose of rifabutin be reduced to 150 mg every other day or three times per week. Patients receiving the combination should also be monitored for liver enzyme elevations and other potential signs and symptoms of rifabutin toxicity such as leukopenia, uveitis, arthralgia, and skin discoloration. Plasma concentration monitoring of rifabutin may be considered. Rifabutin should not be used with saquinavir mesylate in the absence of ritonavir as a pharmacokinetic booster. In addition, unboosted saquinavir is not indicated as the sole protease inhibitor in the treatment of HIV-infected adults; it should only be given with low-dose ritonavir in combination with other antiretroviral agents. In general, treatment of tuberculosis (TB) and Mycobacterium avium-intracellulare complex in the context of antiretroviral therapy is complex and requires an individualized approach. Experts in the treatment of these conditions should be consulted.