Picard Nicolas, Bergan Stein, Marquet Pierre, van Gelder Teun, Wallemacq Pierre, Hesselink Dennis A, Haufroid Vincent
*Service de Pharmacologie, Toxicologie et Pharmacovigilance, CHU Limoges, France; †School of Pharmacy, University of Oslo and Department of Pharmacology, Oslo University Hospital, Norway; Departments of ‡Hospital Pharmacy; §Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands; and ¶Louvain Centre for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain and Department of Clinical Chemistry, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
Ther Drug Monit. 2016 Apr;38 Suppl 1:S57-69. doi: 10.1097/FTD.0000000000000255.
In association with therapeutic drug monitoring of immunosuppressive drugs, pharmacogenetics has rapidly emerged as an additional tool to refine dose selection or, more interestingly to select, a priori, the first dose to administer. Pharmacogenetic biomarkers are now readily available in most transplantation centers, at a limited cost and within a limited analytical time frame, which make them compatible with the clinical decision process. However, despite some evidence of clear associations between polymorphisms in genes encoding metabolizing enzymes (CYP3A4/3A5, UGT1A9) or drug transporters (ABCB1, ABCC2, SLCO1B1) and pharmacokinetics of several immunosuppressive drugs, pre-emptive genotyping and selection of the optimal starting dose based on the genetic background of the patient is still rarely performed in clinical practice. The main reason is probably the lack of formal proof that clinical outcome really improves after genotype-based dosing. So far, the only clinical recommendation in relation to pharmacogenetic biomarkers should be a doubling of the starting tacrolimus dose in patients who are CYP3A5 expressers, and even in this case, some authors still do not recommend pre-emptive genotyping but only genotype-based adaptation if the CYP3A5 genotype is already known. However, with the rise of new technologies, as next generation sequencing, allowing to obtain pre-emptive genetic information, one must be aware that the question will no longer be whether to genotype or not but rather whether or not to use the information already there. There was therefore a need to update the information available in relation to pharmacogenetic biomarkers for calcineurin inhibitors, mycophenolic acid, and mammalian target of rapamycin inhibitors.
随着免疫抑制药物治疗药物监测的开展，药物遗传学迅速成为一种辅助工具，用于优化剂量选择，或者更有意思的是，预先选择首次给药剂量。目前，大多数移植中心都能以有限的成本和在有限的分析时间内轻松获得药物遗传学生物标志物，这使得它们与临床决策过程相契合。然而，尽管有证据表明编码代谢酶（CYP3A4/3A5、UGT1A9）或药物转运体（ABCB1、ABCC2、SLCO1B1）的基因多态性与几种免疫抑制药物的药代动力学之间存在明确关联，但在临床实践中，基于患者遗传背景的预先基因分型和最佳起始剂量选择仍很少进行。主要原因可能是缺乏正式证据证明基于基因型给药后临床结局确实得到改善。到目前为止，关于药物遗传学生物标志物的唯一临床建议是，对于CYP3A5表达者，将他克莫司起始剂量加倍，即便如此，一些作者仍然不建议进行预先基因分型，而是仅在已知CYP3A5基因型的情况下进行基于基因型的剂量调整。然而，随着新技术（如下一代测序）的兴起，能够获得预先的遗传信息，人们必须意识到问题将不再是是否进行基因分型，而是是否使用已有的信息。因此，有必要更新有关钙调神经磷酸酶抑制剂、霉酚酸和雷帕霉素靶蛋白抑制剂的药物遗传学生物标志物的现有信息。
