PuSH - Publikationsserver des Helmholtz Zentrums München: Translational modeling of BTZ-043 in predicting phase IIA efficacy and evaluating drug-drug interactions with BPaL in murine models.

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Ngara, B.* ; Flori, L.* ; van Wijk, R.C.* ; Ernest, J.P.* ; Tyagi, S.* ; Soni, H.* ; Hölscher, C.* ; Walter, K.* ; Dreisbach, J.* ; Hoelscher, M. ; Nuermberger, E.L.* ; Savic, R.*

Translational modeling of BTZ-043 in predicting phase IIA efficacy and evaluating drug-drug interactions with BPaL in murine models.

J. Infect. Dis. 231, e901-e911 (2025)

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INTRODUCTION: BTZ-043 is a promising novel drug candidate for anti-tuberculosis treatment. This study aimed to apply a previously developed mouse-to-human translational modeling platform for anti-tuberculosis drugs to predict phase IIA 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 two-compartmental and direct Emax models, respectively. The model-based prediction of efficacy in humans was comparable to the observed phase IIA efficacy. Single-compartmental models, developed separately, best described the mouse-pharmacokinetic data for bedaquiline, pretomanid, and linezolid in combotherapy. Co-administration 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 BPaL is co-administered with BTZ-043. CONCLUSION: The translational modeling platform adequately predicted the efficacy of BTZ-043 monotherapy. In the absence of drug-drug interactions, co-administration of BTZ-043 with bedaquiline, pretomanid, and linezolid in combotherapy is predicted to improve treatment efficacy.

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