Pharmacokinetic and Pharmacodynamic Study of High-Dose Rifapentine and Moxifloxacin for Treatment of Tuberculosis

Overview

The Tuberculosis Trials Consortium (TBTC) Study 31 is a phase 3 trial evaluating rifapentine-containing regimens for treatment-shortening of drug-susceptible pulmonary tuberculosis. This pharmacokinetic/pharmacodynamic (PK/PD) substudy evaluates rifapentine and moxifloxacin exposure-response relationships for efficacy and safety outcomes. Intensive and sparse PK sampling are performed among participants receiving rifapentine-containing regimens. PK and clinical outcomes data are used to characterize population pharmacokinetics and assess relationships between drug exposure, culture conversion, treatment failure or relapse, and adverse events.

This pharmacokinetic/pharmacodynamic (PK/PD) substudy is conducted within TBTC Study 31, a phase 3 randomized trial evaluating rifapentine-containing regimens for treatment-shortening of drug-susceptible pulmonary tuberculosis. The substudy evaluates population pharmacokinetics and exposure-response relationships for rifapentine and moxifloxacin administered in rifapentine-containing multidrug regimens. Rifapentine is administered at a daily dose of 1200 mg with food, with or without moxifloxacin. Participants undergo intensive and sparse pharmacokinetic sampling between Weeks 2 and 8 of treatment. Intensive PK sampling includes serial plasma collections over approximately 24 hours in a subset of participants, with additional later sampling performed after at least 14 days. Sparse PK sampling is performed in the remaining Study 31 participants. Population PK models are developed using nonlinear mixed-effects methods to estimate individual exposure parameters including area under the concentration-time curve (AUC0-24) and maximum concentration (Cmax). PK/PD analyses evaluate relationships between drug exposure and efficacy outcomes, including culture conversion and treatment failure or relapse, as well as safety outcomes including grade 3 or higher adverse events. The study also evaluates the effect of covariates including demographic and clinical factors on rifapentine and moxifloxacin pharmacokinetics.