Díaz-Villamarín Xando, Nieto-Sánchez María Teresa, Martínez-Pérez María, Novo-González Paula, Fernández-Varón Emilio, Torres-García Alicia, González Astorga Beatriz, Blancas Isabel, Cabeza-Barrera José, Morón Rocío
Instituto de Investigación Biosanitaria de Granada (Ibs. Granada), 18012 Granada, Spain.
Hospital Pharmacy, Hospital Universitario San Cecilio, 18016 Granada, Spain.
Pharmaceutics. 2025 Apr 22;17(5):542. doi: 10.3390/pharmaceutics17050542.
Irinotecan is used in monotherapy or combined with other drugs for treating different cancer streams. SN-38, the active metabolite of irinotecan, is 70% inactivated by the uridine diphosphate (UDP) glucuronosyltransferase family 1 member A1 (UGT1A1) enzyme. The 6 (rs4148323) and (rs3064744) alleles in the gene encoding the enzyme lead to decreased enzyme expression and increased severe irinotecan toxicity. Carrying one or two copies of these alleles results in a UGT1A1 intermediate or poor metabolizer status (IM, PM). The Food and Drug Administration (FDA)-approved drug labels and European Medicines Agency (EMA) European Public Assessment Report (EPAR) for irinotecan recommend dose adjustments based on genotypes, but only for UGT1A1 PM patients. However, available pharmacogenetic (PGx) dosing guidelines for the -irinotecan interaction lack a consensus about considered genetic variants, genotype-translated phenotypes, and therapeutic recommendations. We aimed to describe evidence regarding the impact of the genotype in irinotecan toxicity to inform irinotecan-dosing recommendations based on possible genotypes. : A systematic review was performed to find all the Phase I clinical trials looking for the maximum tolerated dose (MTD) or dose-limiting toxicities (DLTs) of irinotecan depending on the genotype. : Toxicity-related events and the MTD of irinotecan differ among UGT1A1 normal metabolizers (NM), IM, and PM patients considering the and/or * variants. : Dose adjustments might also be recommended for UGT1A1 IM patients ( or genotypes), with a 15% dose reduction considered.
伊立替康可用于单药治疗或与其他药物联合治疗不同类型的癌症。伊立替康的活性代谢产物SN-38有70%被尿苷二磷酸（UDP）葡萄糖醛酸基转移酶家族1成员A1（UGT1A1）酶灭活。编码该酶的基因中的6（rs4148323）和（rs3064744）等位基因会导致酶表达降低，并增加伊立替康的严重毒性。携带这些等位基因的一个或两个拷贝会导致UGT1A1代谢中间型或代谢不良型状态（IM，PM）。美国食品药品监督管理局（FDA）批准的伊立替康药物标签以及欧洲药品管理局（EMA）的欧洲公共评估报告（EPAR）建议根据基因型进行剂量调整，但仅适用于UGT1A1 PM患者。然而，现有的关于伊立替康相互作用的药物遗传学（PGx）给药指南在考虑的基因变异、基因型转化的表型和治疗建议方面缺乏共识。我们旨在描述关于UGT1A1基因型对伊立替康毒性影响的证据，以便根据可能的UGT1A1基因型为伊立替康给药建议提供信息。方法：进行了一项系统评价，以查找所有根据UGT1A1基因型寻找伊立替康最大耐受剂量（MTD）或剂量限制性毒性（DLT）的I期临床试验。结果：考虑UGT1A1和/或变异，伊立替康的毒性相关事件和MTD在UGT1A1正常代谢者（NM）、IM和PM患者中有所不同。结论：对于UGT1A1 IM患者（*或基因型）也可能建议进行剂量调整，可考虑降低15%的剂量。
