3 years ago

Verapamil increases the bioavailability and efficacy of bedaquiline but not clofazimine in a murine model of tuberculosis.

Kala Barnes-Boyle, Si-Yang Li, Eric Nuermberger, Deepak V Almeida, Rokeya Tasneen, Yu Lu, Charles A Peloquin, Jian Xu
Drug efflux pumps play an important role in intrinsic and acquired drug resistance. Verapamil, an efflux inhibitor that enhances the activity of bedaquiline, clofazimine and other drugs against Mycobacterium tuberculosis has been proposed as a potential adjunctive agent for treatment of tuberculosis (TB). However, the extent to which verapamil enhances in vivo efficacy by inhibiting bacterial efflux pumps versus inhibiting mammalian drug transporters to improve oral bioavailability has not been delineated. We found that verapamil potentiated the in vitro activity of bedaquiline and clofazimine against M. tuberculosis clinical isolates, including those harboring rv0678 mutations. Verapamil increased the efficacy of bedaquiline in a murine TB model by the same extent to which it increased systemic bedaquiline exposure. However, verapamil showed no effect on oral bioavailability or efficacy of clofazimine in mice. Addition of verapamil increased the sterilizing activity of a regimen comprised of bedaquiline, clofazimine and pyrazinamide. These results confirm that verapamil has adjunctive activity in vivo, but also demonstrate that its adjunctive effect is likely due to enhanced systemic exposure to companion drugs via effects on mammalian transporters rather than inhibition of bacterial pumps. Therefore, there may be no advantage to administering verapamil compared to increasing doses of companion drugs.

Publisher URL: http://doi.org/10.1128/AAC.01692-17

DOI: 10.1128/AAC.01692-17

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