UCSF

Tuberculosis was the leading infectious disease killer, prior to the COVID-19 pandemic, and infected approximately 10 million people each year and kills approximately 1.5 million. Currently. drug-susceptible TB is treated with rifampin, isoniazid, pyrazinamide, and ethambutol for a minimum of six months, however even with full adherence to this long treatment, relapse and treatment failure each occur in approximately 5-10% of cases. Crucially, these treatments for drug-susceptible TB have not appreciably changed in over 50 years and current drug discovery and clinical development pipelines are in dire need of rapid innovation. In 2020, a landmark phase 3 trial successfully demonstrated noninferiority of a novel 4-month regimen compared to the current 6-month standard of care. TBTC Study 31/A5349 was a multicenter randomized controlled phase 3 non-inferiority trial that compared two four-month regimens (both replace rifampin with rifapentine, and one tests the additional substitution of ethambutol replaced by moxifloxacin) with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis. The regimen containing high dose rifapentine, moxifloxacin, isoniazid, and pyrazinamide successfully demonstrated noninferiority. Remarkably, Study 31/A5349 collected study wide pharmacokinetic samples of all six drugs offering us the first opportunity in the history of TB-research to link drug exposures to long term clinical outcomes. Each of the six drugs were analyzed by non-linear mixed effects modeling and the typical population pharmacokinetic behavior, between subject variability of F, CL, and Vc, and their relationships with clinical characteristics and demographic covariates were thoroughly characterized. Model derived maximal plasma concentration and area under the curve (exposure) were then used in pharmacodynamic efficacy and toxicity analyses to determine optimal dosing. We conducted an integrated analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data from 2343 participants with drug-susceptible tuberculosis from Study 31/A5349. We compared two 4-month rifapentine-based regimens with and without moxifloxacin to a 6-month control regimen. We demonstrated the importance of achieving a high exposure to rifapentine in the 4-month rifapentine-moxifloxacin regimen to reduce the risk of TB-related unfavorable outcomes. We identified a low-risk subgroup where further treatment shortening and simplification is likely possible and a high-risk subgroup where longer treatment may be needed. The integrated models built from this work were used in a variety of simulation work, (1) optimal dosing of the rifapentine-moxifloxacin regimen, (2) design of a novel risk-stratification duration-randomization phase II trial, (3) development of a clinical trial simulation tool to calculate statistical power and determine sample size, and (4) optimization of adaptive trial designs for phase II and III anti-tuberculosis agent. Collectively, the dissertation research described here contributes to the optimal use of the first 4-month regimen for drug-susceptible tuberculosis and develops simulation tools for future development of novel therapeutics and interventions for the treatment and prevention of tuberculosis.