Abstract

This study aimed to develop the population pharmacokinetics (PopPK) model of isoniazid (INH) and its metabolite acetylisoniazid (AcINH) in Vietnamese tuberculosis (TB) patients. Using a nonlinear mixed-effects modeling approach with Monolix, the pharmacokinetics of INH and AcINH were characterized, while covariates were selected via the Conditional Sampling for Stepwise Approach based on Correlation tests (COSSAC). The analysis included 132 TB patients aged 16 years or older who were treated under Vietnam’s National Tuberculosis Program. INH was best described by a two-compartment model with first-order absorption (including lag time) and elimination, while AcINH followed a one-compartment model with first-order elimination. The inclusion of covariates significantly improved the model fit, as evidenced by a reduction in the Akaike information criterion (AIC) from 1,308 to 1,115.3 (?AIC = 192.7). Significant covariates included N-acetyltransferase 2 (NAT2) acetylator phenotype, body weight, dose-to-weight ratio, and sex, all of which were found to influence key pharmacokinetic parameters. Final parameter estimates exhibited acceptable precision, with relative standard errors of ≤35.2% for fixed effects and ≤14.7% for interindividual variability. Model validation through goodness-of-fit plots, prediction error plots, visual predictive checks, and normalized prediction distribution error plots confirmed good predictive performance and agreement with observed data. Overall, this robust PopPK model of INH and AcINH, incorporating NAT2 acetylator phenotype and clinical covariates, supports the application of model-informed precision dosing to optimize INH therapy and reduce toxicity in genetically diverse populations.

Key words: Isoniazid, acetylisoniazid, NAT2 genotype, population pharmacokinetic model, tuberculosis.