Institute of Research and Biomedical Innovation (IRIB), Italian National Council (CNR), Catanzaro, Italy.
Department of Clinical and Experimental Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.
Clin Transl Sci. 2021 Jan;14(1):113-119. doi: 10.1111/cts.12869. Epub 2020 Oct 22.
Interindividual variability in drug efficacy and toxicity is a major challenge in clinical practice. Variations in drug pharmacokinetics (PKs) and pharmacodynamics (PDs) can be, in part, explained by polymorphic variants in genes encoding drug metabolizing enzymes and transporters (absorption, distribution, metabolism, and excretion) or in genes encoding drug receptors. Pharmacogenomics (PGx) has allowed the identification of predictive biomarkers of drug PKs and PDs and the current knowledge of genome-disease and genome-drug interactions offers the opportunity to optimize tailored drug therapy. High-throughput PGx genotyping, from targeted to more comprehensive strategies, allows the identification of PK/PD genotypes to be developed as clinical predictive biomarkers. However, a biomarker needs a robust process of validation followed by clinical-grade assay development and must comply to stringent regulatory guidelines. We here discuss the methodological challenges and the emerging technological tools in PGx biomarker discovery and validation, at the crossroad among molecular genetics, bioinformatics, and clinical medicine.
药物疗效和毒性的个体间差异是临床实践中的一个主要挑战。药物药代动力学（PKs）和药效动力学（PDs）的变化部分可以用编码药物代谢酶和转运体（吸收、分布、代谢和排泄）或编码药物受体的基因中的多态性变体来解释。药物基因组学（PGx）已经允许识别药物 PKs 和 PDs 的预测生物标志物，并且当前关于基因组-疾病和基因组-药物相互作用的知识提供了优化定制药物治疗的机会。从靶向到更全面的策略的高通量 PGx 基因分型允许鉴定 PK/PD 基因型，作为临床预测生物标志物。然而，生物标志物需要经过严格的验证过程，然后进行临床级别的检测开发，并且必须符合严格的监管指南。我们在这里讨论了在分子遗传学、生物信息学和临床医学的交叉点，PGx 生物标志物发现和验证中的方法学挑战和新兴技术工具。
