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

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 (AUC(0–∞)) of 28.9 ± 4.7 μg · h/ml. In the presence of antacids, subjects had a mean C(max) of 3.3 ± 0.5 μg/ml, T(max) of 2.9 ± 1.2 h, and AUC(0–∞) 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 AUC(0–∞) of 29.6 ± 4.7 μg · h/ml. These reductions in C(max), delays in T(max), and modest reductions in AUC(0–∞) can be avoided by giving EMB on an empty stomach whenever possible.