Variability in the population pharmacokinetics of pyrazinamide in South African tuberculosis patients

Objective: This study was designed to characterize the population pharmacokinetics of pyrazinamide in South African pulmonary tuberculosis patients, with special reference to interindividual and interoccasional variability (IIV and IOV, respectively). Methods: Concentration-time measurements obtained from 227 patients receiving oral doses of pyrazinamide were pooled to create a dataset containing 3,092 data points spanning multiple dosing occasions. The software program NONMEM was used to analyze the data. Results: A one-compartment model with first-order absorption, including a zero-order component describing release from formulation, and first-order elimination best described the data. The absorption rate constant was estimated to be bimodally distributed between two distinct subgroups, fast and slow, in approximately even proportion. Absorption rate was threefold greater in fast absorbers (3.56 h(-1)) in comparison to slow absorbers (1.25 h(-1)). Typical values of oral clearance and apparent volume of distribution were estimated as 3.42 L h(-1) and 29.2 l, respectively. IOV was supported in oral clearance (0.0238, variance) and absorption rate (0.623, variance). The duration of zero-order absorption was estimated as 0.290 h, and was quite variable between patients (0.957, variance). Conclusion: The absorption of pyrazinamide in the studied population was highly variable and two separate subpopulations were identified. IOV accounted for a proportion of the variability in clearance and the absorption rate constant.