Intracellular Pharmacodynamic Modeling Is Predictive of the Clinical Activity of Fluoroquinolones against Tuberculosis

Donnellan, Samantha; Aljayyoussi, Ghaith; Moyo, Emmanuel; Ardrey, Alison; Martinez-Rodriguez, Carmen; Ward, Stephen A.; Biagini, Giancarlo A.

Abstract

Clinical studies of new antitubercular drugs are costly and time-consuming. Owing to the extensive tuberculosis (TB) treatment periods, the ability to identify drug candidates based on their predicted clinical efficacy is vital to accelerate the pipeline of new therapies. Recent failures of preclinical models in predicting the activity of fluoroquinolones underline the importance of developing new and more robust predictive tools that will optimize the design of future trials. Here, we used high-content imaging screening and pharmacodynamic intracellular (PDi) modeling to identify and prioritize fluoroquinolones for TB treatment. In a set of studies designed to validate this approach, we show moxifloxacin to be the most effective fluoroquinolone, and PDi modeling-based Monte Carlo simulations accurately predict negative culture conversion (sputum sterilization) rates compared to eight independent clinical trials. In addition, PDi-based simulations were used to predict the risk of relapse. Our analyses show that the duration of treatment following culture conversion can be used to predict the relapse rate. These data further support that PDi-based modeling offers a much-needed decision-making tool for the TB drug development pipeline.

Citation

Donnellan, S., Aljayyoussi, G., Moyo, E., Ardrey, A., Martinez-Rodriguez, C., Ward, S. A., & Biagini, G. A. (2020). Intracellular Pharmacodynamic Modeling Is Predictive of the Clinical Activity of Fluoroquinolones against Tuberculosis. Antimicrobial Agents and Chemotherapy, 64(1), https://doi.org/10.1128/aac.00989-19

• Journal Article Type: Article
• Acceptance Date: Sep 18, 2019
• Online Publication Date: Dec 20, 2019
• Publication Date: 2020-01
• Deposit Date: Feb 11, 2021
• Publicly Available Date: Feb 11, 2021
• Journal: Antimicrobial Agents and Chemotherapy
• Print ISSN: 0066-4804
• Electronic ISSN: 1098-6596
• Publisher: American Society for Microbiology
• Peer Reviewed: Peer Reviewed
• Volume: 64
• Issue: 1
• DOI: https://doi.org/10.1128/aac.00989-19
• Keywords: PDi, infectious disease, pharmacodynamics, pharmacokinetics, preclinicaldrug studies, tuberculosis
• Public URL: http://researchrepository.napier.ac.uk/Output/2718367