PII-093 - TRANSLATIONAL MODELING OF BTZ-043 IN PREDICTING PHASE IIA EFFICACY AND EVALUATION OF DRUG-DRUG INTERACTIONS WITH BPAL IN MURINE MODELS

B. Ngara¹, J. Ernest², R. Van Wijk³, J. Dreisbach⁴, E. Nuermberger⁵, M. Hoelscher⁶, R. Savic^7,8; ¹University of California San Francisco, San Francisco, California, USA, ²UCSF, San Francisco, California, USA, ³Leiden University, Leiden, Zuid-Holland, Netherlands, ⁴LMU University Hospital Munich, Munich, Germany, ⁵Johns Hopkins University, Johns Hopkins University, USA, ⁶LMU, Munich, Germany, ⁷University of California, San Francisco, San Francisco, CA, United States, ⁸UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, CA, United States.

Background: BTZ-043 is among the promising novel drug candidates for optimizing anti-tuberculosis (TB) drug regimens. This study aims to apply a previously developed mouse-to-human translational modeling platform for anti-TB drugs to predict Phase IIA trial outcomes for BTZ-043 in humans and evaluate drug-drug interactions with drugs comprising the BPaL regimen in mice.

Methods: This study performed modeling and simulation of pharmacokinetic (PK) and pharmacodynamic (PD) data from previously conducted mouse experiments for BTZ043 monotherapy and combotherapy with bedaquiline (B), pretomanid (Pa), and linezolid (L). This study also utilized published clinical PK parameters for BTZ-043 monotherapy. The translational modeling platform for anti-TB drugs was applied to predict bacterial colony-forming units (CFU/mL) over time to measure early bacterial activity (EBA) in humans treated with BTZ-043. The preclinical PKPD model and simulations were used to determine drug-drug interactions with BTZ-043 and its impact on the efficacy of the BPaL regimen.

Results: The mouse PK and PKPD data for BTZ-043 monotherapy were best described by two-compartmental PK with saturated absorption kinetics and direct Emax PKPD models, respectively. The mouse-to-human translational model-based prediction of CFU in humans was comparable to what was observed in a Phase IIA clinical trial. The one-compartmental PK model best described the mouse PK data for all the BPaL drugs in combotherapy modeled separately, and co-administration with BTZ-043 was associated with at least a 2-fold reduction in the BPaL drugs exposure. Simulating a 2-fold decrease in exposure of the BPaL drugs when combined with BTZ, predicted a CFU decline comparable to BPaL, indicating BTZ-043’s contribution to the BPaL+BTZ regimen.

Conclusion: The previously developed mouse-to-human translational modeling platform for predicting Phase IIA outcomes for anti-TB drugs in humans accurately predicted EBA for BTZ-043 monotherapy. In the absence of drug-drug interactions, BTZ-043 may improve the efficacy of the BPaL regimen in mice. Further studies in mice with BPaL dosing adjustments or separating the BTZ043 dosing in time to account for drug-drug interactions are required to determine the potential benefit of BTZ-043 when combined with BPaL.