Pharmacokinetics of Ethionamide Administered under Fasting Conditions or with Orange Juice, Food, or Antacids

Abstract

This study was conducted in order to (i) determine the effect of food, orange juice, or antacids on the absorption of a single oral 500-mg dose of ethionamide (ETA) in healthy volunteers, including an assessment of bioequivalence, and (ii) determine ETA population pharmacokinetic (PK) parameters. The pharmacokinetics of ETA in serum was determined for 12 healthy males and females in a randomized, four-period crossover study. Volunteers received single 500-mg doses of ETA either on an empty stomach (reference) or with food, orange juice, or antacids. Serum samples were collected for 48 h and assayed by high-performance liquid chromatography. Data were analyzed by noncompartmental and population methods. Mean test/reference ratios and 90% confidence intervals were determined. No statistically significant differences were seen in the maximum concentration of ETA (C max ), time to maximum concentration (T max ), or area under the concentration-time curve from 0 h to infinity (AUC 0-ؕ ) between the four treatments (P > 0.05 by analysis of variance). The least-squares mean ratios (with confidence intervals in parentheses) for C max were 105% (81.2 to 135%) after orange juice, 94% (72.8 to 121%) after food, and 88% (68.4 to 114%) after antacids. The least-squares mean ratios (with confidence intervals is in parentheses) for AUC 0-ؕ were 91% (72.7 to 115%) after orange juice, 96% (76.4 to 121%) after food, and 95% (75.5 to 120%) after antacids. The mean T max was slightly prolonged following antacid or food administration (2.3 to 2.6 h) compared to administration on an empty stomach or with juice (1.7 to 1.9 h). The median population PK parameters were as follows: K a ‫؍‬ 0.37 to 0.48 h ؊1 , V/F ‫؍‬ 2.0 to 2.8 liters/kg, CL/F ‫؍‬ 56.5 to 72.2 liters/h, and terminal half-life ‫؍‬ 1.7 to 2.1 h, where K a is the absorption rate constant, V is the volume of distribution, and CL is clearance. The PK behavior of ETA was not significantly modified by the different conditions studied. Mean ratios for AUC ranged from 0.91 to 0.96 for the orange juice, food, and antacid treatments, indicating a minimal effect on relative bioavailability. ETA can, therefore, be administered with food if tolerance is an issue.Ethionamide (ETA) is a bacteriostatic, isonicotinic acidderived antituberculosis agent (10, 28). It is used in combination for the treatment of clinical tuberculosis that has failed to respond to adequate first-line therapy (1). Very limited information exists in the literature regarding the pharmacokinetics (PK) of ETA in healthy volunteers or in patients with tuberculosis. ETA is often administered with meals to reduce gastrointestinal intolerance (1). However, to our knowledge, the effects of food, as well as those of antacids or acidic beverages on the PK of ETA have not been evaluated in a crossover study. We have previously demonstrated that food has minimal effect on the absorption of ethambutol and pyrazinamide, while antacids should be avoided near the time of ethambutol dosing (17, 18). Similarly, we have found that ...

Pharmacokinetics of Ethionamide in Children

“…In adults, significant intra-and interindividual variations in ETH serum concentrations have been reported (2,19,21), consistent with our findings. Although in the youngest children, the observed variability might be partly attributable to difficulties in taking medication, we observed similar variability in older children, where no such difficulties were experienced.…”

“…The same principles are the reason for the more rapid elimination of ETH in children than in adults. In studies of ETH pharmacokinetics in adults, a k el of 0.4/h and a corresponding elimination half-life of 1.6 to 1.8 h has been reported (2,29). In our study, the mean half-life in children below 2 years of age was approximately 1 h and increased with age.…”

“…ETH is distributed with ease throughout the body (28). In adults, peak plasma concentrations of ETH occur at approximately 2 h postdosing (2,10,29). For clinical purposes, the suggested serum levels for susceptible strains of Mycobacterium tuberculosis vary in the literature, as follows: 2.5 g/ml or between 1 and 5 g/ml (13,14,22).…”

“…They are oral drugs recommended for treatment of multidrug-resistant tuberculosis (MDR-TB) and also used to treat drug-susceptible tuberculous meningitis (TBM) and miliary disease due to good cerebrospinal fluid penetration (8,19). Absorption of ETH from the intestinal tract is almost complete, and food and antacids appear to have little effect on this process (2). Protein binding is approximately 30% (9).…”

Pharmacokinetics and tissue distribution studies of orally administered nanoparticles encapsulated ethionamide used as potential drug delivery system in management of multi-drug resistant tuberculosis

“…Furthermore, ethionamide is a poorly tolerated drug and often administered with meals to reduce gastrointestinal intolerance (Bass et al, 1994). Ethionamide also undergoes first pass metabolism which reduces its oral bioavailability (Auclair et al, 2001). Enteric-coated ethionamide tablets were developed in an attempt to improve tolerability; however, no significant reduction in gastrointestinal intolerance was found (Weinstein et al, 1962;Gronroos & Toivanen, 1964).…”