Rifampin and Rifabutin Drug Interactions

Rifampin is a potent inducer of the hepatic and intestinal cytochrome P-450 (CYP) enzyme system and the P-glycoprotein (P-gp) transport system, which results in numerous clinically significant drug interactions. A few well-documented, clinically significant, interactions include interactions with cyclosporine, glucocorticoids, ketoconazole or itraconazole, HIV-related protease inhibitors (PIs), zidovudine, delavirdine mesylate, nifedipine, and midazolam. Recent reports demonstrate interactions with numerous other drugs, such as tacrolimus, ondansetron hydrochloride, dapsone, azithromycin, clarithromycin, fluconazole, itraconazole and opiates. Because of the importance of rifampin in treating tuberculosis in patients with AIDS, clinicians need to be cognizant of these interactions. (Rifamycin derivatives have different CYP3A induction potencies. In vitro data demonstrate that rifampin is the most potent, followed by rifapentine and rifabutin. Initial clinical evidence indicated rifabutin reduces serum concentrations of antiretroviral agents, but less so than rifampin. The drug interactions between rifabutin and PIs and nonnucleoside reverse transcriptase inhibitors (NNRI) are easier to manage than those with rifampin. The PIs and NNRIs not only are CYP3A substrates but are also inhibitors and inducers of this same isoform, with the result of either an increase or a decrease of rifabutin levels, frequently necessitating rifabutin and PI dosage adjustment.)

When combined with amprenavir in healthy volunteers, rifabutin given at the standard dose of 300 mg/d was associated in a study with poor tolerability and resulted in leukopenia in 7 of 11 subjects. This abnormally high rate of adverse reactions could have been caused by the nearly 3-fold increase in rifabutin's area under the concentration-time curve (AUC). For this reason, the rifabutin dose must be decreased and/or the dosing interval increased when coadministered with a PI. Another study found that even after adjusting the rifabutin and antiretroviral agent doses, rifabutin levels were suboptimal among many patients taking more than one PI or PIs combined with efavirenz. However, another study found that after rifabutin and PI doses were adjusted, rifabutin levels were not clinically significantly lower in patients receiving either indinavir or nelfinavir mesylate based on highly active antiretroviral therapy (HAART).

Among NNRIs, a drug interaction between a nucleoside and rifampin decreased the zidovudine AUC by 32 percent and 47 percent, respectively. A dramatic reduction (25-95 percent) in the AUC of PIs and NNRIs occurs when rifampin is coadministered because of CYP3A/P-gp induction.

While a ritonavir-saquinavir combination dosed at 400mg each twice daily given with rifampin resulted in adequate levels of saquinavir, newer methods of dosing this combination (ritonavir, 100mg/d, and saquinavir, 1,600mg/d; or ritonavir, 100mg, and saquinavir, 1,000mg, both twice daily) are being used, which may result in a different magnitude of interaction with rifampin. Indeed, one study found that rifampin administered with 100mg of ritonavir and 800mg of indinavir, twice daily, resulted in a greatly reduced indinavir AUC. Efavirenz levels were significantly lowered when given with rifampin at the usual efavirenz dose of 600mg, but were increased to the normal range when the efavirenz dose was increased to 800mg, a strategy that proved successful.

As rifabutin use continues to increase in patients with HIV/AIDS, drug interactions with this agent are increasingly being reported. Although rifabutin interactions are generally less dramatic than rifampin interactions, many are clinically relevant. Whenever clinicians prescribe therapy with either rifampin or rifabutin, it is prudent to screen for drug interactions. As these agents continue to be used, discovery of new interactions should be anticipated.

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