Ethionamide population pharmacokinetics/pharmacodynamics and therapeutic implications in South African adult patients with drug‐resistant tuberculosis

Abstract

Introduction Ethionamide is part of the drug‐resistant tuberculosis regimen whose pharmacokinetic (PK) and pharmacodynamic (PD) information is limited. The aim of the study was to describe the PK and simulate doses to assess PD attainment. Methods This was an observational population PK study of patients admitted for drug‐resistant tuberculosis at a hospital in South Africa. Nonlinear mixed‐effects modelling implemented in Monolix 2019R2 was used to estimate population pharmacokinetic parameters. We performed Monte Carlo simulations to assess and optimise the dose regimen. The target Cmax range was 2.5‐5 μg/mL, which is within the minimum inhibitory concentration (MIC) range. The target AUC0‐24h was 140.5 μg*h/mL, which corresponds to the PK/PD target ratio AUC0‐24h/MIC of 56.2. Results A one‐compartment pharmacokinetic model with a lag‐time, first‐order absorption and elimination best described the PK of ethionamide. The lag‐time, absorption rate constant (ka), volume of distribution (V/F) and clearance (Cl/F) were 0.66 hours, 0.434 h−1, 180 L and 99.5 L/h, respectively, for a typical individual weighing 52.6 kg. Between‐subject variability in lag‐time, ka, V/F and Cl/F were 38%, 92%, 168% and 120%, respectively. Simulation of the recommended doses of 15‐20 mg/kg, 500 mg, 750 mg and 1000 mg for patients in the weight bands <33, 33‐50, 51‐70 and >70 kg resulted in <17% and 3% of the patients achieving the target Cmax and AUC0‐24h, respectively. Conclusion There is high variability in ethionamide PK and very few patients attain the desired target exposure at standard or optimised doses. We propose individualised dose regimen optimisation.

Molecular Determinants of Ethionamide Resistance in Clinical Isolates of Mycobacterium tuberculosis

“…Currently, the approved concentration is 5 mg/L, while most ethionamide naïve isolates have a MIC < 2.5 mg/L. This value also better fits previously published pharmacokinetic data [ 34 , 35 , 36 ]. However, the overlap of MIC distributions between resistant and susceptible isolates reflects only the ‘intermediate’ resistance of isolates with MIC = 5 mg/L, and further clinical studies of ethionamide treatment effectiveness in such cases are needed.…”

“…In conclusion, determination of ethionamide MIC before treatment is highly desirable, taking into account the inability to increase doses due to drug toxicity. Furthermore, a large individual variation of pK/pD parameters [ 36 ] and interaction with other drugs [ 35 , 44 ] require personalized treatment with therapeutic drug monitoring.…”