Lesion penetration predicts tuberculosis treatment shortening through a validated translational tool to de-risk development

Abstract

Abstract Anti-tuberculosis (TB) drugs must reach the disease site to be effective, but complex TB pathology limits drug distribution and efficacy, as bacteria in the necrotic center of lung cavities are difficult to access and kill. Our study generates the most comprehensive database of site-of-disease distribution for 24 drugs and drug candidates in a rabbit model of cavitary TB. We validate a lung lesion penetration model with clinical data and develop an integrated approach that combines microenvironment-specific pharmacokinetics and pharmacodynamics. Next, we simulate site-of-disease coverage of shortened regimens tested in major Phase 3 trials over the past decade, allowing direct comparisons with trial outcomes. We propose that regimens including at least two drugs achieving bactericidal concentrations in pulmonary cavities are more likely to meet primary clinical endpoints in patients with cavitary disease. Our translational platform constitutes a validated tool to support drug evaluation, smart regimen design, and de-risking of late-stage trials.