Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, 576104, India.
Eur J Drug Metab Pharmacokinet. 2024 Sep;49(5):541-557. doi: 10.1007/s13318-024-00910-7. Epub 2024 Aug 17.
Due to interindividual variability in drug metabolism and pharmacokinetics, traditional isoniazid fixed-dose regimens may lead to suboptimal or toxic isoniazid concentrations in the plasma of patients with tuberculosis, contributing to adverse drug reactions, therapeutic failure, or the development of drug resistance. Achieving precision therapy for isoniazid requires a multifaceted approach that could integrate various clinical and genomic factors to tailor the isoniazid dose to individual patient characteristics. This includes leveraging molecular diagnostics to perform the comprehensive profiling of host pharmacogenomics to determine how it affects isoniazid metabolism, such as its metabolism by N-acetyltransferase 2 (NAT2), and studying drug-resistant mutations in the Mycobacterium tuberculosis genome for enabling targeted therapy selection. Several other molecular signatures identified from the host pharmacogenomics as well as other omics-based approaches such as gut microbiome, epigenomic, proteomic, metabolomic, and lipidomic approaches have provided mechanistic explanations for isoniazid pharmacokinetic variability and/or adverse drug reactions and thereby may facilitate precision therapy of isoniazid, though further validations in larger and diverse populations with tuberculosis are required for clinical applications. Therapeutic drug monitoring and population pharmacokinetic approaches allow for the adjustment of isoniazid dosages based on patient-specific pharmacokinetic profiles, optimizing drug exposure while minimizing toxicity and the risk of resistance. Current evidence has shown that with the integration of the host pharmacogenomics-particularly NAT2 and Mycobacterium tuberculosis genomics data along with isoniazid pharmacokinetic concentrations in the blood and patient factors such as anthropometric measurements, comorbidities, and type and timing of food administered-precision therapy approaches in isoniazid therapy can be tailored to the specific characteristics of both the host and the pathogen for improving tuberculosis treatment outcomes.
由于药物代谢和药代动力学的个体间差异，传统的异烟肼固定剂量方案可能导致肺结核患者血浆中的异烟肼浓度不理想或有毒，从而导致药物不良反应、治疗失败或耐药性的发展。实现异烟肼的精准治疗需要采取多方面的方法，将各种临床和基因组因素整合起来，根据个体患者的特点来调整异烟肼的剂量。这包括利用分子诊断技术对宿主药物基因组学进行全面分析，以确定其如何影响异烟肼的代谢，例如 N-乙酰转移酶 2（NAT2）对其的代谢，以及研究结核分枝杆菌基因组中的耐药突变，以实现靶向治疗选择。从宿主药物基因组学中确定的其他几个分子特征以及其他基于组学的方法，如肠道微生物组、表观基因组学、蛋白质组学、代谢组学和脂质组学方法，为异烟肼药代动力学变异性和/或药物不良反应提供了机制解释，从而可能促进异烟肼的精准治疗，尽管需要在更大和更多样化的结核病人群中进行进一步验证才能应用于临床。治疗药物监测和群体药代动力学方法允许根据患者特定的药代动力学特征调整异烟肼剂量，优化药物暴露，同时最大限度地降低毒性和耐药风险。目前的证据表明，通过整合宿主药物基因组学——特别是 NAT2 和结核分枝杆菌基因组学数据以及血液中的异烟肼药代动力学浓度以及患者因素，如人体测量学、合并症和给予食物的类型和时间——精准治疗方法可以根据宿主和病原体的特定特征来调整异烟肼治疗，以改善结核病治疗结果。
