Pharmacokinetics of Ethambutol under Fasting Conditions, with Food, and with Antacids

Abstract

Ethambutol (EMB) is the most frequent “fourth drug” used for the empiric treatment of Mycobacterium tuberculosis and a frequently used drug for infections caused by Mycobacterium avium complex. The pharmacokinetics of EMB in serum were studied with 14 healthy males and females in a randomized, four-period crossover study. Subjects ingested single doses of EMB of 25 mg/kg of body weight under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. Serum was collected for 48 h and assayed by gas chromatography-mass spectrometry. Data were analyzed by noncompartmental methods and by a two-compartment pharmacokinetic model with zero-order absorption and first-order elimination. Both fasting conditions produced similar results: a mean (± standard deviation) EMB maximum concentration of drug in serum (C max) of 4.5 ± 1.0 μg/ml, time to maximum concentration of drug in serum (T max) of 2.5 ± 0.9 h, and area under the concentration-time curve from 0 h to infinity (AUC0–∞) of 28.9 ± 4.7 μg · h/ml. In the presence of antacids, subjects had a mean C maxof 3.3 ± 0.5 μg/ml, T max of 2.9 ± 1.2 h, and AUC0–∞ of 27.5 ± 5.9 μg · h/ml. In the presence of the Food and Drug Administration high-fat meal, subjects had a mean C max of 3.8 ± 0.8 μg/ml, T max of 3.2 ± 1.3 h, and AUC0–∞ of 29.6 ± 4.7 μg · h/ml. These reductions in C max, delays inT max, and modest reductions in AUC0–∞ can be avoided by giving EMB on an empty stomach whenever possible.

Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring

“…The oral bioavailability of pyrazinamide is almost complete; the cumulative urinary excretion of pyrazinamide and its main metabolites after administration of a single oral dose (27 mg/ kg) to healthy subjects is approximately 73 % [42]. Food may delay the oral absorption of pyrazinamide but does not have a significant effect on the extent of absorption [12,40]. The plasma protein binding of pyrazinamide is low; values of 10 to 40 % have been reported [34,43].…”

“…Following oral administration, maximum plasma concentrations of ethambutol are reached after approximately 2 to 3 h [45][46][47]. Results of various studies indicate that the absolute oral bioavailability of ethambutol is approximately 80 % [47,48].…”

“…Results of various studies indicate that the absolute oral bioavailability of ethambutol is approximately 80 % [47,48]. Food does not significantly affect C max and AUC of ethambutol compared to administration in the fasted state [46,49,50]. Ethambutol binding to plasma proteins in healthy subjects and patients with tuberculosis has been shown to be between 10 and 30 % [11,48].…”

“…Following oral administration, maximum plasma concentrations of pyrazinamide are reached after 1 to 2 h [40,41]. The oral bioavailability of pyrazinamide is almost complete; the cumulative urinary excretion of pyrazinamide and its main metabolites after administration of a single oral dose (27 mg/ kg) to healthy subjects is approximately 73 % [42].…”

HIV–TB Drug Interactions

“…Various data have suggested an interaction with aluminum-magnesium antacids, leading to a reduction in plasma ethambutol concentrations [59].…”