| DOI: 10.29090/psa.2026.03.25.9140 | Pharm Sci Asia 2026; 53(3), 294-308 |
Pharmacokinetic modeling and simulation of isoniazid dosing for different N-acetyltransferase 2 phenotypes in Thai tuberculosis patientsThanakorn Surarak1,5, Pramote Tragulpiankit, Surakameth Mahasirimongkol2, Hutcha Sriplung3, Usanee Ungcharoen4, Wichit Nosoongnoen1*
1 Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
2 Information and Communication Technology Center, Ministry of Public Health, Nonthaburi, Thailand
3 Epidemiology Unit, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
4 Division of Tuberculosis, Department of Disease control, Ministry of Public Health, Bangkok, Thailand
5 Division of Pharmacology, Department of Preclinical Science, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
The metabolism of isoniazid (INH) is influenced by N-acetyltransferase 2 (NAT2) genetic polymorphisms, which regulate its acetylation rate. This study aimed to optimize INH dosages for Thai patients with tuberculosis (TB) based on their NAT2 phenotypes. INH plasma concentrations were measured using HPLC-MS/MS. Pharmacokinetic (PK) parameters, including the absorption constant (ka), apparent volume of distribution (Vd/F), and elimination constant (ke) were estimated via population PK modeling with Phoenix? NLME software. A one-compartment model with first-order absorption and elimination was employed using the FOCE ELS algorithm. Covariate analysis indicated that the PK of INH was substantially influenced by the NAT2 phenotype and body weight. Model selection was guided by -2LL, AIC, and BIC statistics, while model validation was evaluated via goodness-of-fit plots, bootstrap analysis, and visual predictive checks. Subsequently, Monte Carlo simulations in Oracle? Crystal Ball software were used to predict plasma INH concentrations for each NAT2 phenotype. The study suggested optimal daily INH dosages to achieve therapeutic plasma levels of 3–6 ?g/mL: 225-250 mg for slow acetylators (SA), 275-300 mg for intermediate acetylators (IA), and 400-450 mg for rapid acetylators (RA). These dosage adjustments aim to improve treatment efficacy and reduce drug toxicity risks. By tailoring dosages to the NAT2 phenotype, this pharmacogenetic approach enhances the safety and effectiveness of TB therapy, offering a valuable framework for personalized medicine, particularly in genetically diverse populations like Thai patients.
Keyword:
Isoniazid; NAT2 phenotype; Pharmacokinetic-pharmacodynamic simulation; Modeling
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