To determine intrasubject and intersubject variability in, and the effects of food and antacids on, the pharmacokinetics of pyrazinamide (PZA).Design.
Randomized, four-period, crossover phase I study.Subjects.
Fourteen healthy men and women volunteers.Interventions.
Subjects ingested single doses of PZA 30 mg/kg under fasting conditions twice, without a high-fat meal and with an aluminummagnesium antacid. They also received standard dosages of isoniazid, rifampin, and ethambutol.Measurements and Main Results.
Serum was collected for 48 hours and assayed by gas chromatography with mass selective detector. Data were analyzed by noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: mean PZA Cmax 53.4 ± 10.4 μg/ml, Tmax 1.43 ± 1.06 hours, and AUC0-∞ 673 ± 79.7 μg·hr/ml. Fasting results are similar to those in previous reports. In the presence of antacids, subjects had a mean Cmax of 55.6 ± 9.0 μg/ml, Tmax of 1.43 ± 1.23 hours, and AUC0-∞ of 628 ± 88.4 μg∞hr/ml. In the presence of the high-fat meal, mean Cmax was 45.6 ± 9.44 μg/ml, Tmax 3.09 ± 1.74 hours, and AUC0-∞ 687 ± 116 μg·hr/ml.Conclusions.
These small changes in Cmax, Tmax, and AUC0-∞. can be avoided by giving PZA on an empty stomach whenever possible.