Ethambutol Population Pharmacokinetics and Pharmacodynamics from a Phase 3 Confirmatory Trial for the Treatment of Tuberculosis

Abstract

Background: Ethambutol, a longstanding treatment for tuberculosis, lacks comprehensive pharmacokinetic data, particularly regarding covariates affecting exposure and their link to treatment outcomes. Using the largest data to date from Study 31/AIDS Clinical Trials Group A5349, we aimed to characterize ethambutol pharmacokinetics, identify risk factors for lower exposure, quantify relationships between exposure and efficacy and safety outcomes, and explore dosing considerations that optimize risks and benefits. Methods: We analyzed ethambutol pharmacokinetic data using nonlinear mixed-effect modeling. We evaluated the contribution of ethambutol exposure to efficacy outcomes using parametric time-to-event modeling and safety outcomes using logistic regression. Results: In 1,493 participants with 3,077 plasma samples, a one-compartment model with first-order elimination best described ethambutol pharmacokinetics, with diabetes, higher creatinine clearance, and higher weight linked to increased clearance. Higher ethambutol exposure was modestly associated with grade 3 or higher adverse events and a reduced risk of tuberculosis-related unfavorable outcomes. Target exposures for 95% cure were 8.9 µg∙h/mL in the 6-month control regimen and 25.6 µg∙h/mL in the 4-month rifapentine regimen. Simulations showed that reducing doses in middle (1200 to 1000 mg) and highest (1600 to 1200 mg) weight-bands could equalize median exposures, lowering toxicity risk while maintaining efficacy in the control regimen, but might not achieve target exposure in the rifapentine regimen. Conclusion: The contribution of ethambutol exposure is regimen-dependent, with a higher efficacy target required for the 4-month rifapentine regimen. Dose reductions for patients above 55 kg may mitigate toxicity in standard therapy but risk compromising efficacy in the shorter regimen.