Predictive Modeling to Study the Treatment-Shortening Potential of Novel Tuberculosis Drug Regimens, Toward Bundling of Preclinical Data. (19th February 2021)

• Record Type: Journal Article
• Authors: Mudde, Saskia E; Ayoun Alsoud, Rami; van der Meijden, Aart; Upton, Anna M; Lotlikar, Manisha U; Simonsson, Ulrika S H; Bax, Hannelore I; de Steenwinkel, Jurriaan E M
• Is Part Of: Journal of infectious diseases. Volume 225:Number 11(2022)
• Page Start: 1876
• Page End: 1885
• Publication Date: 2021-02-19
• Subjects: tuberculosis -- mouse -- pharmacokinetics -- pharmacodynamics -- treatment duration; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiab101
• Languages: English
• ISSNs: 0022-1899

Abstract

Abstract: Background: Given the persistently high global burden of tuberculosis, effective and shorter treatment options are needed. We explored the relationship between relapse and treatment length as well as interregimen differences for 2 novel antituberculosis drug regimens using a mouse model of tuberculosis infection and mathematical modeling. Methods: Mycobacterium tuberculosis– infected mice were treated for up to 13 weeks with bedaquiline and pretomanid combined with moxifloxacin and pyrazinamide (BPaMZ) or linezolid (BPaL). Cure rates were evaluated 12 weeks after treatment completion. The standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) was evaluated as a comparator. Results: Six weeks of BPaMZ was sufficient to achieve cure in all mice. In contrast, 13 weeks of BPaL and 24 weeks of HRZE did not achieve 100% cure rates. Based on mathematical model predictions, 95% probability of cure was predicted to occur at 1.6, 4.3, and 7.9 months for BPaMZ, BPaL, and HRZE, respectively. Conclusion: This study provides additional evidence for the treatment-shortening capacity of BPaMZ over BPaL and HRZE. To optimally use preclinical data for predicting clinical outcomes, and to overcome the limitations that hamper such extrapolation, we advocate bundling of available published preclinical data into mathematical models. Abstract : By combining the evaluation of treatment efficacy of anti-tuberculosis drug regimens in a mouse tuberculosis infection model with mathematical modeling, it was found that BPaMZ had a higher treatment-shortening potential than BPaL, compared to the standard HRZE regimen.