In Vitro Evaluation of Drug-Drug Interaction Potential of Epetraborole, a Novel Bacterial Leucyl-tRNA Synthetase Inhibitor.

Abstract

Epetraborole (EBO) is a boron-containing inhibitor of bacterial leucyl-tRNA synthetase, with potent activity against nontuberculous mycobacteria (NTM) and Gram-negative bacteria, including Burkholderia pseudomallei. EBO is being developed for the treatment of NTM lung disease and melioidosis, administered in combination with other therapeutic agents in both diseases. Therefore, EBO and its major circulating metabolite M3 were evaluated in comprehensive drug-drug interaction (DDI) in vitro studies. The CYP inhibitory and substrate potential of EBO and M3 were assessed using hepatic microsomes. Stably transfected cells that expressed individual efflux or uptake transporters were used to determine whether EBO or M3 were substrates or inhibitors for these receptors. Stability studies indicated that EBO is a poor substrate for major CYP enzymes. Neither EBO nor M3 was a potent reversible or time-dependent inhibitor of major CYP enzymes. EBO was not an inducer of CYP1A2 mRNA, while it was a weak inducer of CYP2B6 and CYP3A4. EBO was a substrate only for OCT2. At clinically relevant concentrations, neither EBO nor M3 inhibited major human efflux or uptake transporters. Based on these data, at clinically relevant concentrations of EBO and M3, there is a low risk of victim or perpetrator DDI.