PII-022 - RIFAPENTINE EXPOSURE-RESPONSE RELATIONSHIPS ARE DIFFERENT FOR PHASE II AND PHASE III PRIMARY EFFICACY ENDPOINTS IN TUBERCULOSIS CLINICAL TRIALS.

A. Xu, V. Chang, B. Solans, R. Savic; University of California, San Francisco, San Francisco, CA, USA.

Background: Phase III endpoint for tuberculosis is disease relevant unfavorable outcomes up to 18 months. Due to the prolonged follow up period, numerous biomarkers have been used as endpoints in Phase II studies. Phase IIA outcome is time to positivity (TTP) up to 2 weeks of treatment, while Phase IIB outcome is stable sputum culture conversion (TCC) after 8 weeks of treatment. The goal of this work is to compare exposure-response relationships for rifapentine across trial outcomes.

Methods: Phase II and III data were integrated for the entire development pathway for rifapentine. We modeled exposure-response relationships of various outcomes with non-linear mixed effects modeling. Exposure was described as the area under the curve (AUC) at steady state. Longitudinal TTP and TCC in Phase II Study 29/29X were evaluated. In Phase III Study 31, time to TB-related unfavorable outcome was evaluated.

Results: A linear model described the relationship between rifapentine exposure and change in TTP. A sigmoidal Emax model described the relationship between exposure and TCC and a target exposure was found to be 350 ug*h/mL to achieve maximal drug effect. A sigmoidal Emax model also described the relationship between exposure and time to TB-related unfavorable outcomes. The target exposure to achieve less than 5% TB-related unfavorable outcomes was higher at 570 ug*h/mL. Further analysis also revealed different exposure-response relationships for different phenotypes.

Conclusion: The target rifapentine exposures determined with Phase II and Phase III endpoints differed by 1.6-fold. This raises major challenges for future research when translating results from Phase II trials to inform Phase III trials. A better link between intermediate microbiologic outcomes and long-term clinical outcomes are needed.