A systematic efficacy analysis of tuberculosis treatment with BPaL-containing regimens using a multiscale modeling approach.

Autor: Budak M; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Via LE; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Maryland, USA.; Tuberculosis Imaging Program, Division of Intramural Research, NIAID, Bethesda, Maryland, USA., Weiner DM; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Maryland, USA.; Tuberculosis Imaging Program, Division of Intramural Research, NIAID, Bethesda, Maryland, USA., Barry CE 3rd; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Maryland, USA.; Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, Observatory, Republic of South Africa.; Department of Medicine, University of Cape Town, Observatory, Republic of South Africa., Nanda P; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Michael G; Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA., Mdluli K; Bill & Melinda Gates Medical Research Institute, Cambridge, Massachusetts, USA., Kirschner D; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Jazyk: angličtina
Zdroj: CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2024 Apr; Vol. 13 (4), pp. 673-685. Date of Electronic Publication: 2024 Feb 26.
DOI: 10.1002/psp4.13117
Abstrakt: Tuberculosis (TB) is a life-threatening infectious disease. The standard treatment is up to 90% effective; however, it requires the administration of four antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol [HRZE]) over long time periods. This harsh treatment process causes adherence issues for patients because of the long treatment times and a myriad of adverse effects. Therefore, the World Health Organization has focused goals of shortening standard treatment regimens for TB in their End TB Strategy efforts, which aim to reduce TB-related deaths by 95% by 2035. For this purpose, many novel and promising combination antibiotics are being explored that have recently been discovered, such as the bedaquiline, pretomanid, and linezolid (BPaL) regimen. As a result, testing the number of possible combinations with all possible novel regimens is beyond the limit of experimental resources. In this study, we present a unique framework that uses a primate granuloma modeling approach to screen many combination regimens that are currently under clinical and experimental exploration and assesses their efficacies to inform future studies. We tested well-studied regimens such as HRZE and BPaL to evaluate the validity and accuracy of our framework. We also simulated additional promising combination regimens that have not been sufficiently studied clinically or experimentally, and we provide a pipeline for regimen ranking based on their efficacies in granulomas. Furthermore, we showed a correlation between simulation rankings and new marmoset data rankings, providing evidence for the credibility of our framework. This framework can be adapted to any TB regimen and can rank any number of single or combination regimens.
(© 2024 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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