POPULATION PHARMACOKINETICS MODEL OF PYRAZINAMIDE TO OPTIMIZE TUBERCULOSIS TREATMENT: AN INTERETHNIC COHORT STUDY OF DIABETES MELLITUS EFFECT ON DRUG EXPOSURE

초록

BACKGROUND: The current WHO-recommended doses for tuberculosis (TB) patients follow one-dose-fits-all, neglecting the ethnicity effect. Nonetheless, the previous pharmacokinetics (PK) studies of pyrazinamide (PZA) showed potential interethnic differences among populations. We aim to evaluate factors related to interindividual variability (IIV) and interethnic differences in the PK of PZA between Korean and Indonesian patients with TB. METHODS: Data on demographics, clinical characteristics, and PZA concentrations were collected from 22 Korean hospitals and one Indonesian hospital as part of a multinational prospective cohort study aiming to develop personalized pharmacotherapy for TB patients. A total of 320 adult TB patients with 407 concentrations, comprising 160 Korean patients and 160 Indonesian patients, were used for model development. Population PK models were developed using the nonlinear mixed-effect method. Visual predictive check and nonparametric bootstrap were carried out for internal validation. A Monte Carlo dose simulation was performed sequentially. RESULTS: A one-compartment model with allometric scaling using lean body weight adequately described the PK of PZA. Internal validation of the model showed good performance. The PK parameters of PZA did not show significant inter-ethnicity differences. There were 23% and 26% increases in apparent clearance (CL/F) of Indonesian patients with diabetes mellitus (DM) (CL/FIndonesian 3.18 L/h) and Korean patients aged >65 years with DM (CL/FKorean 3.5 L/h). Considering both efficacy (AUC0-24 h > 363 mg/L) and toxicity targets (Cmax <60 mg/L) of PZA, doses of 1,000–1,250 mg for patients of bodyweight <40 kg and 1,250 mg for older patients with DM in this weight band had a 90% probability of target attainment. CONCLUSION: There was an insignificant difference in the PK of PZA between Korean and Indonesian patients. DM influenced the IIV of PZA CL/F for both ethnicities, with a greater effect in older patients. We recommend a higher dose of PZA for patients of body weight < 40 kg and older patients with DM in this weight band. Due to the potential adverse reaction of PZA in high doses, a follow-up study with a larger sample size should be conducted to validate our suggestions. Our model can be implemented for model-informed precision dosing-based therapeutic drug monitoring in both ethnicities.