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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., DOI: 10.1093/infdis/jiaf088 (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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Btz-043 ; Drug Interactions ; Early Bacterial Activity ; Phase Iia Prediction ; Translational Pkpd ; Tuberculosis; C3heb/fej Mice; Tuberculosis; Kinetics

ISSN (print) / ISBN 0022-1899

e-ISSN 1537-6613

Journal Journal of Infectious Diseases, The

Publisher Oxford University Press

Publishing Place Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Global Health (UGH)

Grants Nederlandse Organisatie voor Wetenschappelijk Onderzoek
TB Alliance
German Center for Infection Research
European and Developing Countries Clinical Trials Partnership 2 program
German Ministry for Education and Research
German Center for Infection Research InfectControl
Bavarian Ministry for Science and the Arts
Swiss State Secretariat for Education, Research, and Innovation
National Institutes of Health, National Institute of Allergy and Infectious Diseases