Population Pharmacokinetics of Pyrazinamide in Patients with Tuberculosis

The current treatment used for tuberculosis (TB) is lengthy and needs to be shortened and improved. Pyrazinamide (PZA) has potent sterilizing activity and has the potential to shorten the TB treatment duration, if treatment is optimized. The goals of this study were (i) to develop a population pharmacokinetic (PK) model for PZA among patients enrolled in PK substudies of Tuberculosis Trial Consortium (TBTC) trials 27 and 28 and (ii) to determine covariates that affect PZA PK. (iii) We also performed simulations and target attainment analysis using the proposed targets of a maximum plasma concentration (C-max) of > 35 mu g/ml or an area under the concentration-versus-time curve (AUC) of > 363 mu g.h/ml to see if higher weight-based dosing could improve PZA efficacy. Seventy-two patients participated in the substudies. The mean (standard deviation [SD]) C-max was 30.8 (7.4) mu g/ml, and the mean (SD) AUC from time zero to 24 h (AUC(0-24)) was 307 (83) mu g.h/ml. A one-compartment open model best described PZA PK. Only body weight was a significant covariate for PZA clearance. Women had a lower volume of distribution (V/F) than men, and both clearance (CL/F) and V/F increased with body weight. Our simulations show that higher doses of PZA (> 50 mg/kg of body weight) are needed to achieve the therapeutic target of an AUC/MIC of > 11.3 in > 80% of patients, while doses of > 80 mg/kg are needed for target attainment in 90% of patients, given specific assumptions about MIC determinations. For the therapeutic targets of a C-max of > 35 mu g/ml and/or an AUC of > 363 mu g.h/ml, doses in the range of 30 to 40 mg/kg are needed to achieve the therapeutic target in > 90% of the patients. Further clinical trials are needed to evaluate the safety and efficacy of higher doses of PZA.