Pharmacokinetics of isoniazid under fasting conditions, with food, and with antacids

STUDY OBJECTIVES: To determine the intra- and intersubject variability in and the effects of food or antacids on the pharmacokinetics of isoniazid (INH). DESIGN: Randomized, four-period cross-over Phase I study in 14 healthy male and female volunteers. Subjects ingested single doses of INH 300 mg under fasting conditions twice, with a high-fat meal, and with aluminum- magnesium antacid. They also received standard doses of rifampin, pyrazinamide, and ethambutol. RESULTS: Serum was collected for 48 hours, and assayed by high performance liquid chromatography (HPLC). Data were analyzed using noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: a mean INH C(max) of 5.53 ± 2.92 μg/ml, T(max) of 1.02 ± 1.10 hours, and AUC(0-∞) of 20.16 ± 12.45 μg* hr/ml. These findings are similar to those reported previously. Antacids did not alter these parameters significantly (C(max) of 5.62 ± 2.53 μg/ml, T(max) of 0.71 ± 0.56 hours, and AUC(0-∞) of 20.27 ± 11.39 μg* hr/ml). In contrast, the high-fat meal recommended by the Food and Drug Administration reduced INH C(max) by 51% (2.73 ± 1.70 μg/ml), nearly doubled T(max) (1.93 ± 1.61 hours), and reduced AUC(0-∞) by 12% (17.72 ± 10.32 μg*hr/ml). CONCLUSIONS: These changes in C(max), T(max), and AUC(0-∞) can be avoided by giving INH on an empty stomach whenever possible.