Pharmacology Department. University of Granada (UGR), Granada, Spain; Pfizer - University of Granada, Junta de Andalucía Centre for Genomics and Oncological Research (GENYO), Granada, Spain.
Neurology Department, Hospital Universitario Clínico San Cecilio-Instituto de Investigación Biosanitaria de Granada (ibs.Granada), Granada, Spain.
Biomed Pharmacother. 2022 Sep;153:113536. doi: 10.1016/j.biopha.2022.113536. Epub 2022 Aug 12.
Multiple sclerosis is a chronic inflammatory neurological disease, and siponimod (Mayzent) is the first oral treatment option for adult patients with secondary progressive multiple sclerosis. We performed a systematic review of the pharmacogenetics of Siponimod, and we found that (430 C>T; rs1799853) and CYP2C9 * 3 (1075 A>C; rs1057910), both translated no-function alleles, have been related to a lower metabolism of siponimod by CYP2C9 enzyme. The FDA-approved drug label and EMA risk management plan for siponimod require testing patients for CYP2C9 genotype before treatment starts. The FDA drug label states that siponimod is contraindicated in patients carrying a CYP2C9 * 3/* 3 genotype, and a daily maintenance dose of 1 mg in patients with CYP2C9 * 1/* 3 and * 2/* 3 genotypes. The EMA reported the potential long-term safety implications in CYP2C9 poor metabolizer patients treated with this drug. Based on this systematic review we concluded that CYP2C9 SNPs influence on siponimod response might be stated by assessing not only CYP2C9 * 2 and CYP2C9 * 3 but other genetic variants resulting in CYP2C9 IM/PM status. CYP2C9 IM phenotype translated from the CYP2C9 * 2 genotype should be revised since it is contradictory compared to other CYP2C9 no-function alleles, and CYP2C9 * 2 might be excluded from PGx testing recommendation before treatment starts with siponimod since it is not translated into a therapeutic recommendation.
多发性硬化症是一种慢性炎症性神经系统疾病，西尼莫德（Mayzent）是治疗成人继发进展型多发性硬化症的第一种口服治疗选择。我们对西尼莫德的药物遗传学进行了系统评价，发现（430C>T；rs1799853）和 CYP2C93（1075A>C；rs1057910）均为无功能等位基因，与 CYP2C9 酶对西尼莫德的代谢降低有关。FDA 批准的西尼莫德药物标签和 EMA 风险管理计划要求在开始治疗前对患者进行 CYP2C9 基因型检测。FDA 药物标签指出，携带 CYP2C93/3 基因型的患者禁用西尼莫德，而 CYP2C91/3 和 2/3 基因型的患者每日维持剂量为 1mg。EMA 报告了在接受该药物治疗的 CYP2C9 弱代谢患者中潜在的长期安全性影响。基于这项系统评价，我们得出结论，CYP2C9 SNPs 对西尼莫德反应的影响可能不仅通过评估 CYP2C92 和 CYP2C93，还可以通过评估导致 CYP2C9 IM/PM 状态的其他遗传变异来确定。从 CYP2C92 基因型翻译而来的 CYP2C9 IM 表型应该进行修正，因为与其他 CYP2C9 无功能等位基因相比，它是矛盾的，并且在开始使用西尼莫德治疗之前，CYP2C9*2 可能被排除在 PGx 测试推荐之外，因为它不会转化为治疗建议。
