Research Article | Volume: 16, Issue: 9, September, 2026

Pharmacokinetic Model of Isoniazid and Acetylisoniazid in Vietnamese Tuberculosis Patients: Effects of NAT2 Acetylator Phenotype and Clinical Covariates

Tuan Anh Le,  Hai Ba Le,  Kien Chi Phung,  Minh Anh Duong Vu,  Thach Hong Nong,  Linh Mai Hoang,  Hiep Minh Le,  Phuong Linh Nguyen,  Hung Manh Pham,  Luyen Thi Le,  Huong Lien Thi Nguyen   

Tuan Anh Le1, Hai Ba Le2, Kien Chi Phung2, Minh Anh Duong Vu2, Thach Hong Nong2, Linh Mai Hoang2, Hiep Minh Le2, Phuong Linh Nguyen2, Hung Manh Pham2, Luyen Thi Le1, Huong Lien Thi Nguyen2

1University of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam.

2Department of Clinical Pharmacy, Hanoi University of Pharmacy, Hanoi, Vietnam.

Open Access   

Published:  Jul 06, 2026

DOI: 10.1177/22313354261457076
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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.


Keyword:     Isoniazid acetylisoniazid NAT2 population pharmacokinetic model tuberculosis

Citation:

Le TA, Le HB, Phung KC, et al. Pharmacokinetic Model of Isoniazid and Acetylisoniazid in Vietnamese Tuberculosis Patients: Effects of NAT2 Acetylator Phenotype and Clinical Covariates. J Appl Pharm Sci. 2026;16(9):854-864. https://doi.org/10.1177/22313354261457076

Copyright: © The Author(s). This open-access article is distributed under the Creative Commons Attribution-NonCommercial 4.0 International License, which permits non-commercial use, sharing, adaptation, distribution, and reproduction in any medium or format, provided appropriate credit is given, a link to the license is included, and any changes are indicated.
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