PII-081 - POPULATION PHARMACOKINETICS (PK) OF ETHAMBUTOL IN TUBERCULOSIS PATIENTS – TUBERCULOSIS TRIALS CONSORTIUM (TBTC) STUDY A5349/S31.

S. Alkhafaji¹, V. Chang¹, R. Savic¹, A. and the Tuberculosis Trials Consortium²; ¹University of California, San Francisco, San Francisco, CA, USA, ²AIDS Clinical Trials Group and the Tuberculosis Trials Consortium, , USA.

Background: Ethambutol (EMB) has been used for over 50 years as one of four drugs in the first-line regimen for treating drug-susceptible TB. Despite the long history of use, EMB literature lacks PK characterization from a large patient population with characterization of covariates to identify patients at risk for low exposure.

Methods: EMB population PK model was built using data from study 31/ACTGA5349 and Nonlinear Mixed Effects Modeling (NONMEM) software. 1547 patients received oral 800mg ( < 55kg), 1200mg (55-75kg), and 1600mg (>75kg) doses of EMB. Overall, 3135 plasma samples were collected at approximately 0.5, 6, and 12 h after dose.

Results: A 1-compartment distribution model with first-order elimination and absorption lag time best described the PK data. In our final model, (1) patients with diabetes had a 10.3% higher clearance and (2) for each 10kg increase in weight, there was a 10.3% increase in clearance. Using raw data from the trial, median exposures for patients receiving 800mg, 1200mg and 1600mg dose were 14.3 µg∙h/mL, 18.9 µg∙h/mL and 21.1 µg∙h/mL, respectively. While weight effect on clearance is needed in the model, patients receiving the 800mg dose in the lowest weight-band have low exposures. Dosing simulations demonstrate that if these patients receive 1000mg, the median exposure would be increased to 18.1 µg∙h/mL.

Conclusion: EMB PK is well described by our model, which identified patients living with diabetes and high weight as factors that decrease EMB exposure. Additionally, participants in the lowest weight-band ( < 55kg) receiving 800mg may benefit from dose adjustment.