Population pharmacokinetics analysis for interethnics comparison of pyrazinamide exposure between Korean and Indonesian patients with tuberculosis

초록

Background and Aims Optimizing drug exposure to improve tuberculosis (TB) treatment outcome was of great importance. TB relapse and drug resistance could be reduced with the refined therapeutic management. Pyrazinamide (PZA) remained as the main component in TB treatment. This study aimed to evaluate the factors that significantly affected the pharmacokinetics (PK) of PZA and investigate interethnic differences in PZA exposure. Methods 845 TB patients with 988 concentrations were enrolled for model establishment. Demographic, clinicaldata, and PZA concentrations from multisite in Korea and Indonesia were collected. The nonlinear mixed effect method was used to develop the population PK model. Results One-compartment model with first-order absorption-elimination and allometric scaling for body size effect described PK of PZA adequately. Ethnicity was found to be a significant covariate in typical clearance (CL/F). Indonesian patients had 40% higher CL/F than Korean patients (CL/F: 4.4 L/h). Additionally, there was a 30% increased in CL/F of 70 years old subjects with DM. Ethnicities did not show any influence on the variability of volume distribution. The model showed good performance through internal and external validation. Conclusion Lean body weight was the most significant covariate in CL/F for both ethnicities. Our result suggested that Indonesian patients had a higher risk for low exposure to PZA than Korean patients. Additionally, more than 70 years old with DM as comorbidity would likely have lower exposure to PZA due to increased CL/F. Our model can be used to optimize drug exposures in both Korean and Indonesian TB patients. Acknowledgements This work was supported by a National Research Foundation of Korea (NRF) grant (No. 2018R1A5A2021242) funded by the Korean government (MSIT).