Population Pharmacokinetic Modelling and Limited Sampling Strategies for Therapeutic Drug Monitoring of Pyrazinamide in Patients with Tuberculosis

Abstract

Pyrazinamide is one of the first-line antituberculosis drugs. The efficacy of pyrazinamide is associated with the ratio of 24-h area under the concentration-time curve (AUC₂₄) to MIC. The objective of this study was to develop and validate a limited sampling strategy (LSS) based on a population pharmacokinetic (popPK) model to predict AUC₂₄. A popPK model was developed using an iterative two-stage Bayesian procedure and was externally validated. Using data from 20 treatment-naive adult tuberculosis (TB) patients, a one compartment model with transit absorption and first-order elimination best described pyrazinamide pharmacokinetics and fed state was the only significant covariate for absorption rate constant (k_a). External validation, using data from 26 TB patients, showed that the popPK model predicted AUC₂₄ with a slight underestimation of 2.1%. LSS were calculated using Monte Carlo simulation (n = 10,000). External validation showed LSS with time points 0 h, 2 h, and 6 h performed best with RMSE of 9.90% and bias of 0.06%. Food slowed absorption of pyrazinamide, but did not affect bioavailability, which may be advantageous in case of nausea or vomiting in which food can be used to diminish these effects. In this study, we successfully developed and validated a popPK model and LSS, using 0 h, 2 h, and 6 h postdose samples, that could be used to perform therapeutic drug monitoring (TDM) of pyrazinamide in TB patients.

Keywords: food; limited sampling strategy; pharmacology; population pharmacokinetics; pyrazinamide; tuberculosis.

FIG 1

Goodness-of-fit plots for the final population pharmacokinetic model of pyrazinamide.

FIG 2

External validation of the popPK model (n = 26). Bland-Altman plot of mean of AUC_{24, ref} and AUC_{24, model} (mg*h/L) versus the difference in % of the mean AUC₂₄. The solid line indicates the mean difference. The corresponding limits of agreement (mean difference ± 2 SD difference) are depicted as dashed lines. Passing-Bablok plot.

FIG 3

Bland-Altman plot of mean of AUC_{24, ref} and AUC_{24, LSS 0–2-6} (mg*h/L) versus the difference in % of the mean AUC₂₄. The solid line indicates the mean difference. The corresponding limits of agreement (mean difference ± 2 SD difference) are depicted as dashed lines.

FIG 4

Target attainment AUC/MIC > 2.79 of model and validation cohort. MIC distributions from references are combined (8, 31, 33).