POPULATION PHARMACOKINETIC MODELING OF ISONIAZID, RIFAMPIN, AND PYRAZINAMIDE

Isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) are the most i mportant drugs for the treatment of tuberculosis (TB). The pharmacokin etics of all three drugs in the plasma of 24 healthy males were studie d as part of a randomized cross-over phase I study of two dosage forms . Subjects ingested single doses of INH at 250 mg, RIF at 600 mg, and PZA at 1,500 mg. Plasma was collected for 36 h and was assayed by high performance liquid chromatography. The data were analysed by noncompar tmental, iterative two-stage maximum a posteriori probability Bayesian (IT2B) and nonparametric expectation maximization (NPEM) population m odelling methods. Fast and slow acetylators of INH had median peak con centrations in plasma (C-max) of 2.44 and 3.64 mu g/ml, respectively, both of which occurred at 1.0 h postdose (time of maximum concentratio ns of drugs in plasma [T-max]), with median elimination half-lives (t( 1/2)) of 1.2 and 3.3 h, respectively (by the NPEM method). RIF produce d a median C-max of 11.80 mu g/ml, a T-max of 1.0 h, and a t(1/2) of 3 .4 h. PZA produced a median C-max of 28.80 mu g/ml, a T-max of 1.0 h, and a t(1/2) of 10.0 h. The pharmacokinetic behaviors of INH, RIF, and PZA were well described by the three methods used. These models can s erve as benchmarks for comparison with models for other populations, s uch as patients with TB or TB with AIDS.