Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan, USA.
Divisions of Clinical Pharmacology & Research in Patient Services, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Clin Pharmacol Ther. 2021 Sep;110(3):589-594. doi: 10.1002/cpt.2312. Epub 2021 Jun 28.
Pharmacogenetics (PGx) seeks to enable selection of the right dose of the right drug for each patient to optimize therapeutic outcomes. Most PGx focuses on pharmacokinetics (PKs), due to our relatively advanced understanding of the genes involved in PKs and the causative effects of variants in those genes. Genetic variants can also affect pharmacodynamics (PDs), but relatively few PGx-PD associations have been identified. This is partially due to a more limited understanding of the relevant genes and the consequences of genetic variation, but is also due in part to the potential confounding of PK variability in assessments of clinical outcomes that have a contribution from both PKs and PDs. For example, it is challenging to confirm the effect of mu opioid receptor (OPRM1) genetic variation on opioid response due to the contribution of CYP2D6 genotype to bioactivation of some opioid drugs (i.e., codeine and tramadol). The objectives of this mini-review are to describe several recent efforts to discover and validate PGx-PD that disentangle the influence of PK variability and propose potential approaches that could be used in future PGx-PD analyses. We use the effect of OPRM1 genetics on opioid response to illustrate how these analyses could be conducted and conclude by discussing how PGx-PD could be translated into clinical practice to improve therapeutic outcomes.
药物遗传学（PGx）旨在为每个患者选择合适剂量的正确药物，以优化治疗效果。由于我们对参与药物代谢动力学（PKs）的基因以及这些基因中的变异的因果作用有相对先进的了解，因此大多数 PGx 都集中在 PKs 上。遗传变异也会影响药效动力学（PDs），但已确定的 PGx-PD 相关性相对较少。这部分是由于对相关基因及其遗传变异后果的了解有限，但部分原因还在于在评估具有 PK 和 PD 两者贡献的临床结果时，PK 变异性的潜在混杂。例如，由于某些阿片类药物（即可待因和曲马多）的生物活化作用受到 CYP2D6 基因型的影响，确认阿片受体（OPRM1）遗传变异对阿片类药物反应的影响具有挑战性。本综述的目的是描述最近发现和验证可分离 PK 变异性影响的 PGx-PD 的几项努力，并提出可用于未来 PGx-PD 分析的潜在方法。我们使用 OPRM1 基因对阿片类药物反应的影响来说明如何进行这些分析，并通过讨论 PGx-PD 如何转化为临床实践以改善治疗效果来结束。
