Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis

Abstract

<jats:p>Ethionamide (ETA), an isonicotinic acid derivative, is part of multidrug-resistant tuberculosis (MDR-TB) regimen. The current guidelines deprioritized ETA due to potential less effectiveness compared to other agents. Our aim was to develop a population pharmacokinetic (PK) model and simulate ETA dosing regimens to assess target attainment. This study included subjects from four different sites, including both healthy volunteers and patients with MDR-TB. The TB centers included were two in the US and one in Bangladesh. Patients who received ETA and had at least one drug concentration reported were included. The population PK model was developed, 1,000-2,250 mg total daily regimens were simulated, and target attainment using published minimum inhibitory concentrations (MICs) and 1.0-log kill and resistance suppression targets were assessed using Pmetrics R package. We included 1,167 ethionamide concentrations from 94 subjects. The final population model was a one-compartment model with first-order elimination and absorption with a lag-time. The mean (SD) final population parameter estimates were: absorption rate constant 1.02 hr<jats:sup>-1</jats:sup> (1.11), elimination rate constant 0.69 hr<jats:sup>-1</jats:sup> (0.46), volume of distribution 104.16 L (59.87), and lag-time 0.43 hr (0.32). Total daily dose of 1,500 mg or more was needed to achieve ≥90% 1.0-log kill target attainment at MIC 1 mg/L, and 2,250 mg/day achieved 80% resistance suppression target attainment at MIC 0.5 mg/L. In conclusion, we developed a population PK model and assessed target attainment for different ETA regimens. Patients may not be able to tolerate the doses needed to achieve the predefined targets supporting current recommendations for ETA deprioritization.</jats:p>

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

“…This is consistent with the studies of Auclair et al and Thee et al, 10,15 who additionally reported significant BSV in plasma concentrations of ethionamide in children with DS‐TB as well as adult healthy volunteers. Similarly, in the study by Al‐Shaer et al, 27 no covariates included in the ethionamide pharmacokinetic model improved the fit or led to a decrease in BSV. FMO3 is the predominant liver enzyme that biotransforms ethionamide into ethionamide sulfoxide 8 .…”

Prothionamide Dose Optimization Using Population Pharmacokinetics for Multidrug-Resistant Tuberculosis Patients

“…To date, only noncompartmental analyses were conducted for PTO, and this study was the first to develop a population PK model of the drug. Meanwhile, population PK models for ETO have been developed from clinical trials of patients with tuberculosis (12)(13)(14). According to previous research, the oral bioavailability of PTO and ETO were 0.9 and 1.1, respectively (5,15).…”

“…The PTO fAUC ss was calculated using noncompartmental analysis of the simulation results by the ncappc package of R software (R Foundation for Statistical Computing, Vienna, Austria) (22). The free fraction was assumed to be 70% (12,23). The range of MIC values for M. tuberculosis was set at 0.8 to 8 mg/mL, as reported by Tan et al (10).…”

“…For the PK/PD target, fAUC ss /MIC values of 10 for 1.0-log kill and 42 for resistance suppression were used, based on the values for ethionamide (12,24). Ethionamide values were used because ethionamide and PTO exhibit similar effects and can be used interchangeably (25).…”

Therapeutic drug monitoring in patients with tuberculosis and concurrent medical problems

“…In order to observe delayed absorption, and to assess elimination, sampling at 2 and 6 hours post dose is suggested [3,141]. A fAUC/ MIC target of 10 has been proposed for 1.0-log kill, which has shown to be attained with daily dose of 750 mg and higher [65,143]. TDM of ethionamide could be useful in order to strive toward PK/PD targets, although patient tolerability often limits doses [143].…”