PHARMACOKINETICS OF PYRAZINAMIDE UNDER FASTING CONDITIONS, WITH FOOD,AND WITH ANTACIDS

Study Objectives. To determine intrasubject and intersubject variabili ty in, and the effects of food and antacids on, the pharmacokinetics o f pyrazinamide (PZA). Design. Randomized, four-period, crossover phase I study. Subjects. Fourteen healthy men and women volunteers. Interve ntions. Subjects ingested single doses of PZA 30 mg/kg under fasting c onditions twice, without a high-fat meal and with an aluminum-magnesiu m antacid. They also received standard dosages of isoniazid, rifampin, and ethambutol. Measurements and Main Results. Serum was collected fo r 48 hours and assayed by gas chromatography with mass selective detec tor. Data were analyzed by noncompartmental methods and a compartmenta l analysis using nonparametric expectation maximization. Both fasting conditions produced similar results. mean PZA C-max 53.4 +/- 10.4 mu g /ml, T-max 1.43 +/- 1.06 hours, and AUC(0-infinity), 673 +/- 79.7 mu g . hr/ml. Fasting results are similar to those in previous reports. In the presence of antacids, subjects had a mean C-max of 55.6 +/- 9.0 m u g/ml, T-max of 1.43 +/- 1.23 hours, and AUC(0-infinity), of 628 +/- 88.4 mu g . hr/ml. In the presence of the high-fat meal, mean C-max wa s 45.6 +/- 9.44 mu g/ml, T-max 3.09 +/- 1.74 hours, and AUC(0-infinity ), 687 +/- 116 mu g . hr/ml. Conclusions. These small changes in C-max T-max and AUCo(0-infinity) can be avoided by giving PZA on an empty s tomach whenever possible.