Translational Modeling of BTZ-043 to Predict Phase 2A Efficacy and Evaluate Drug-Drug Interactions With Bedaquiline, Pretomanid, and Linezolid in Murine Models.

Abstract

Background: BTZ-043 is a promising novel drug candidate for antituberculosis treatment. This study aimed to apply a previously developed mouse-to-human translational modeling platform for antituberculosis drugs to predict phase 2A outcomes for BTZ-043 in humans and evaluate the impact of observed drug-drug interactions on the contribution of BTZ-043 to combotherapy in a mouse model.

Methods: The study utilized data from mouse experiments for BTZ-043 monotherapy and combotherapy with bedaquiline, pretomanid, and linezolid, and clinical information for BTZ-043 monotherapy. The translational models were applied to predict the colony-forming units as a measure of efficacy in humans treated with BTZ-043 monotherapy and evaluate the effect of BTZ-043 on the pharmacokinetics-pharmacodynamics of combotherapy bedaquiline, pretomanid, and linezolid.

Results: The mouse-pharmacokinetic and mouse-pharmacodynamic data for BTZ-043 monotherapy were best described by 2-compartmental and direct Emax models, respectively. The model-based prediction of efficacy in humans was comparable to the observed phase 2A efficacy. Single-compartmental models, developed separately, best described the mouse-pharmacokinetic data for bedaquiline, pretomanid, and linezolid in combotherapy. Coadministration with BTZ-043 was associated with at least a 2-fold reduction in bedaquiline, pretomanid, and linezolid exposures in mice, and model-based simulations suggested that the observed decreases in exposure to these drugs would have resulted in even lower efficacy than what was observed when bedaquiline, pretomanid, and linezolid are coadministered with BTZ-043.

Conclusions: The translational modeling platform adequately predicted the efficacy of BTZ-043 monotherapy. In the absence of drug-drug interactions, coadministration of BTZ-043 with bedaquiline, pretomanid, and linezolid in combotherapy is predicted to improve treatment efficacy. Clinical Trials Registration. NCT0404400.