Dosing of Bedaquiline with Rifamycins reduces Rifabutin Plasma Concentrations

Abstract

Bedaquiline (BDQ), a diarylquinoline mycobacterial ATP synthase inhibitor approved in the United States for drug-resistant tuberculosis, is metabolized by CYP3A4, an hepatic enzyme strongly induced by rifampin (RIF), an essential part of drug-sensitive tuberculosis treatment. BDQ is used more broadly in some other countries and has been evaluated for treatment of non-tuberculosis mycobacterial infections, often in combination with rifabutin (RBT). We examined the pharmacokinetic interactions of BDQ plus either RIF or RBT in 33 healthy volunteers. Subjects were randomly assigned to receive two single 400 mg doses of BDQ, given 29 days apart, and either RBT 300 mg or RIF 600 mg, given daily from day 20 to 41 after the first dose of BDQ. Blood samples were collected prior to dosing and at multiple subsequent time points to measure plasma drug concentrations, including those of the rifamycin primary metabolites. BDQ treatment had little effect on the disposition of RIF but resulted in a dramatic shortening of the half-life of RBT and decreased exposure to it. When the drugs were administered together (Day 29) the peak rifamycin concentrations and peak rifamycin metabolite concentrations were reduced significantly (p <0.001). This appeared to result from reduced absorption and raises a concern that doses of BDQ and the rifamycins, particularly RBT should be staggered when the two drugs are given on the same day. The optimum time between dosing should be determined.