Influence of N-acetyltransferase 2 (NAT2) genotype/single nucleotide polymorphisms on clearance of isoniazid in tuberculosis patients: a systematic review of population pharmacokinetic models.

PURPOSE: Significant pharmacokinetic variabilities have been reported for isoniazid across various populations. We aimed to summarize population pharmacokinetic studies of isoniazid in tuberculosis (TB) patients with a specific focus on the influence of N-acetyltransferase 2 (NAT2) genotype/single-nucleotide polymorphism (SNP) on clearance of isoniazid. METHODS: A systematic search was conducted in PubMed and Embase for articles published in the English language from inception till February 2022 to identify population pharmacokinetic (PopPK) studies of isoniazid. Studies were included if patient population had TB and received isoniazid therapy, non-linear mixed effects modelling, and parametric approach was used for building isoniazid PopPK model and NAT2 genotype/SNP was tested as a covariate for model development. RESULTS: A total of 12 articles were identified from PubMed, Embase, and hand searching of articles. Isoniazid disposition was described using a two-compartment model with first-order absorption and linear elimination in most of the studies. Significant covariates influencing the pharmacokinetics of isoniazid were NAT2 genotype, body weight, lean body weight, body mass index, fat-free mass, efavirenz, formulation, CD4 cell count, and gender. Majority of studies conducted in adult TB population have reported a twofold or threefold increase in isoniazid clearance for NAT2 rapid acetylators compared to slow acetylators. CONCLUSION: The variability in disposition of isoniazid can be majorly attributed to NAT2 genotype. This results in a trimodal clearance pattern with a multi-fold increase in clearance of NAT2 rapid acetylators compared to slow acetylators. Further studies exploring the generalizability/adaptability of developed PopPK models in different clinical settings are required.

Influence of N-acetyltransferase 2 polymorphisms and clinical variables on liver function profile of tuberculosis patients.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the N-acetyltransferase 2 (NAT2) gene as well as several other clinical factors can contribute to the elevation of liver function test values in tuberculosis (TB) patients receiving antitubercular therapy (ATT). RESEARCH DESIGN AND METHODS: A prospective study involving dynamic monitoring of the liver function tests among 130 TB patients from baseline to 98 days post ATT initiation was undertaken to assess the influence of pharmacogenomic and clinical variables on the elevation of liver function test values. Genomic DNA was extracted from serum samples for the assessment of NAT2 SNPs. Further, within this study population, we conducted a case control study to identify the odds of developing ATT-induced drug-induced liver injury (DILI) based on NAT2 SNPs, genotype and phenotype, and clinical variables. RESULTS: NAT2 slow acetylators had higher mean [90%CI] liver function test values for 8-28 days post ATT and higher odds of developing DILI (OR: 2.73, 90%CI: 1.05-7.09) than intermediate acetylators/rapid acetylators. CONCLUSION: The current study findings provide evidence for closer monitoring among TB patients with specific NAT2 SNPs, genotype and phenotype, and clinical variables, particularly between the period of more than a week to one-month post ATT initiation for better treatment outcomes.