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

Introduction 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. Methods 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. Results 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. Conclusion 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.