Predictive modeling to study the treatment-shortening potential of novel tuberculosis drug regimens, towards bundling of preclinical data.

BACKGROUND Given the persistently high global burden of tuberculosis (TB), effective and shorter treatment options are needed. Here, we explore the relationship between relapse and treatment length as well as inter-regimen differences for two novel anti-TB drug regimens using a mouse model of TB 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 cure 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 for BPaMZ, BPaL and HRZE to occur at 1.6, 4.3, and 7.9 months, respectively. CONCLUSION This study provides additional evidence for the treatment-shortening capacity of BPaMZ over BPaL and HRZE. To optimally utilize 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.