The wide variability of isoniazid (INH) pharmacokinetics is mainly attributed to the trimodal N-acetyltransferase 2 (NAT2) acetylator phenotype, i.e., rapid, intermediate, and slow. Consequently, a uniform INH dose in the current clinical practice may lead to treatment failure and drug resistance emergence. There is a lack of studies on specific doses of INH for different NAT2 acetylator phenotypes among tuberculosis patients. Therefore, we aimed to provide insight into the optimal dosing of INH for each NAT2 acetylator phenotype with respect to the probability of achieving a pharmacokinetic (PK)/pharmacodynamic target. PK, NAT2 genotype, and clinical data were collected in a multicenter prospective cohort study conducted at 13 clinical centers in Korea. Population PK modeling and simulation were carried out. Data from 454 TB patients were divided into a training dataset and a test dataset with a ratio of 4 to 1. The PK of the training data were best described by a two-compartment model with allometric scaling for the body size effect. Importantly, NAT2 acetylator phenotypes significantly affected the apparent clearance. Our model provided better predictive performance compared to previously published models, which was evaluated by external validation using the test set. The simulation for assessing the target efficacy and toxicity indicated that the best INH dosing regimens for Korean tuberculosis patients were once-daily doses of 400, 300, and 200 mg for rapid, intermediate, and slow acetylators, respectively. In conclusion, our study provides a step forward in precision dosing for anti-tuberculosis management. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

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