Population pharmacokinetics of isoniazid in adult Indian tuberculosis patients: Evaluation of NAT2 polymorphisms

Gene polymorphisms in N -acetyltransferase 2 ( NAT2 ) contribute to inter-individual variability in isoniazid pharmacokinetics among tuberculosis patients. India is a high tuberculosis-burden country and exhibits substantial genome diversity, which has important implications for precision medicine initiatives in tuberculosis. This study aimed to develop an isoniazid population pharmacokinetics (PopPK) model to elucidate NAT2 genotype-dependent variability in isoniazid clearance, thereby facilitating the advancement of individualized dosing strategies in Indian tuberculosis patients in real-world settings. In this prospective observational study, tuberculosis patients were genotyped for single nucleotide polymorphisms in the NAT2 gene by real-time polymerase chain reaction. Plasma isoniazid concentrations were quantified by liquid chromatography with tandem mass spectrometry. The isoniazid PopPK analysis was performed using the Pumas package in Julia. Isoniazid pharmacokinetics were best described by a two-compartment model with two transit compartments and first-order absorption and elimination. A trimodal distribution pattern in isoniazid clearance was observed across the NAT2 acetylator phenotypes, with estimated values of 36.3 L/h, 23.2 L/h, and 16.5 L/h for rapid, intermediate, and slow acetylators, respectively. Isoniazid clearance was lower in females than in males, and in patients with antitubercular drug-induced liver injury compared to those without. Diabetic tuberculosis patients exhibited higher isoniazid clearance compared to non-diabetic tuberculosis patients. Our NAT2 genotype-integrated PopPK model, developed for adult Indian tuberculosis patients, revealed distinct differences in isoniazid clearance across NAT2 phenotypes; however, these differences were not statistically significant. NAT2 slow acetylators exhibited more than two-fold lower clearance compared to NAT2 rapid acetylators. These findings highlight the potential importance of NAT2 genotype-guided individualized isoniazid dosing strategies in clinical settings. • A NAT2 genotype-integrated population pharmacokinetics (PopPK) model for isoniazid was developed for the first time in adult Indian patients diagnosed with tuberculosis. • Isoniazid pharmacokinetics was adequately explained by a two-compartment model with two transit compartments and first-order absorption and elimination. • NAT2 slow acetylators had more than two-fold lower clearance than NAT2 rapid acetylators, highlighting the need for NAT2 genotype-guided individualized dosing. • Among these tuberculosis patients, isoniazid clearance was lower in females and those with antitubercular drug-induced liver injury, while higher clearance was observed among those with diabetes mellitus, although not statistically significant.