Population pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide

Isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) are the most important drugs for the treatment of tuberculosis (TB). The pharmacokinetics of all three drugs in the plasma of 24 healthy males were studied 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 highperformance liquid chromatography. The data were analysed by noncompartmental, iterative two-stage maximum a posteriori probability Bayesian (IT2B) and nonparametric expectation maximization (NPEM) population modelling methods. Fast and slow acetylators of INH had median peak concentrations 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 concentrations 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 produced 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 serve as benchmarks for comparison with models for other populations, such as patients with TB or TB with AIDS.