Pharmacogenetics of First-Line Antitubercular Drugs: An Update

Background:Tuberculosis (TB) treatment relies on a prolonged first-line antibiotic regimen, including isoniazid, rifampicin (RF), ethambutol (EMB), and pyrazinamide.Pharmacogenetics plays a crucial role in optimizing TB treatment by addressing individual variability in drug metabolism and responses. Genetic polymorphisms can significantly affect pharmacokinetics and therapeutic outcomes. The aim of this review was to explore the role of pharmacogenetics in first-line antibiotics used to treat TB.Methods:We reviewed the literature using PubMed, Scopus, Web of Science, and the Cochrane Library, focusing on articles published in the last 10 years (from December 2014 to December 2024) on the pharmacogenetics of first-line anti-TB drugs. Only English-language studies involving human subjects were included, prioritizing those investigating genetic variants that affect drug bioavailability.Results:In this study, 33 manuscripts were included.N-acetyltransferase 2 Single-nucleotide polymorphisms were associated with different isoniazid acetylation rates, which affect toxicity and efficacy. Genetic variations in CYP2E1, GSTM1, and MnSOD also contribute to hepatotoxicity.For RF, variants in SLCO1B1, ABCB1, PXR, CAR, CES1, and CES2 genes were related to variability in drug absorption, metabolism, and clearance, highlighting the need for personalized dosing strategies. Notably, SLCO1B1 rs4149056 polymorphism is associated with decreased OATP1B1 RF transport activity, potentially leading to increased plasma exposure, whereas other polymorphisms modulate drug exposure and clearance rates. In addition, sex, body weight, and genotype influenced RF pharmacokinetics, suggesting the need for tailored dosing recommendations based on patient characteristics.Similarly, variability in EMB pharmacokinetics is associated with CYP1A2 2159, which is related to a 50% reduction in bioavailability, necessitating dose adjustments in patients coinfected with TB and HIV. Some variants of ABCB1, OATP1B1, PXR, VDR, CYP24A1, and CYP27B1 may further modulate the plasma and intracellular concentrations of EMB, thereby influencing drug efficacy.Conclusions:This review highlights the importance of integrating pharmacogenetic insights into clinical practice to enhance the efficacy of TB treatment, minimize toxicity, and prevent drug resistance. Despite promising evidence, further research and clinical validation are required to implement pharmacogenetics in routine TB management. Future advancements in therapeutic drug monitoring and omics technologies will pave the way for precision medicine in TB therapy.