PII-091 - TRANSLATIONAL TOOL FOR PREDICTING THE EARLY BACTERICIDAL ACTIVITY OF SUTEZOLID FOR THE TREATMENT OF TUBERCULOSIS.
Thursday, March 23, 2023
5:00 PM – 6:30 PM EDT
A. Patel1, Q. Wang1, E. Nuermberger2, R. Savic1; 1University of California, San Francisco, San Francisco, CA, USA, 2Johns Hopkins University, Baltimore, MD, USA.
Graduate Student University of California, San Francisco San Francisco, California, United States
Background: Existing drug regimens for tuberculosis (TB) are limited by lengthy courses and potential toxicities, hindering the ability for strict patient adherence. Thus, there is a need for shorter, effective, and safe regimens for this disease, requiring expedited drug development. To support this, a translational tool that uses preclinical data to predict Phase IIA early bactericidal activity (EBA) of anti-TB drugs in humans was previously developed (1). Here, this tool was applied to the oxazolidinone antimicrobial sutezolid due to its promising role in novel TB regimens. Methods: The translational tool consisted of a mouse pharmacokinetic-pharmacodynamic (PKPD) model incorporating bacterial growth and a mechanistic immune function, using longitudinal data from 270 BALB/c mice treated with sutezolid. Translation to clinical predictions was performed by linking the mouse PKPD model with a population PK model developed from Phase I trial data using a correction for plasma protein binding differences. Clinically relevant doses were simulated and compared with Phase IIA clinical trial (NCT01225640) results, with the goal of achieving predictions < 2-fold from observations. Results: Predicted EBA of sutezolid at 600 mg twice daily (BID) and 1200 mg daily (QD) was consistent with clinical data. Mean predicted change in bacterial colony-forming units (log10 CFU) from baseline to day 14 (EBA 0-14) was -0.077 (95% CI: -0.061 to -0.093) at 600 mg BID and -0.084 (95% CI: -0.072 to -0.096) at 1200 mg QD, whereas observations were -0.088 (95% CI: -0.065 to -0.112) at 600 mg BID and -0.068 (95% CI: -0.045 to -0.090) at 1200 mg QD. Conclusion: Phase IIA trial outcomes for sutezolid were accurately predicted using this translational tool, making it favorable for predicting the EBA of future anti-TB drugs.
1. Zhang N, et al. Mechanistic Modeling of Mycobacterium tuberculosis Infection in Murine Models for Drug and Vaccine Efficacy Studies. Antimicrob. Agents Chemother. 64(3), e01727-19 (2020).