Population Pharmacokinetics Model Development of Isoniazid for Individualizing Tuberculosis Treatment Based on the NAT2 Acetylator Phenotype

Background Because of high early bactericidal activity, Isoniazid (INH) plays a vital role in tuberculosis treatment. Genetic polymorphisms of metabolic enzyme N-acetyltransferase-2 (NAT2) is primarily responsible for a trimodal distribution of INH pharmacokinetics in slow, intermediate, and faster acetylators. The success of INH-based treatment is associated with acetylator in terms of efficacy and toxicity. The purpose of this study was to build a population pharmacokinetic model of INH in Korean patients with tuberculosis considering the NAT2 acetylator phenotype. Method An observational multi-site cohort study is currently being conducted in anti-TB drugs-treated patients at the Center for Personalized Precision Medicine of Tuberculosis (cPMTb). A total of 477 INH plasma samples (380 for the training dataset, 97 for the test dataset) were obtained from 361 patients enrolled in cPMTb. The concentration of INH was measured by a high-performance liquid chromatography. The acetylator phenotype was predicted through single nucleotide polymorphisms in NAT2. The population pharmacokinetic analysis was conducted using NONMEM and R software. Results A two-compartment model with the first order absorption and elimination described accurately the pharmacokinetic profile of INH. The effect of body size was described using allometric scaling and NAT2 acetylator phenotype significantly affected clearance of INH. Clearance was different for each NAT2 acetylator phenotype being 21.3, 16.9, and 8.9 L/h for rapid, intermediate, and slow acetylators, respectively. Through the application of the model, we performed an external validation using the test dataset and provided percentage of achieving therapeutic target over different dose of isoniazid for each NAT2 acetylator phenotype. Conclusion We combined the NAT2 acetylator phenotype to establish a population pharmacokinetic model for INH among Korean tuberculosis patients. Our findings suggest that dose adjustment according to NAT2 acetylator phenotype may be needed.