Kweekel Dinemarie, Guchelaar Henk-Jan, Gelderblom Hans
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Cancer Treat Rev. 2008 Nov;34(7):656-69. doi: 10.1016/j.ctrv.2008.05.002. Epub 2008 Jun 16.
Irinotecan is a topo-isomerase-I inhibitor with broad antitumor activity in solid tumors. Its use may lead to severe toxicities, predominantly neutropenia and diarrhea which can be life-threatening. This review discusses clinical determinants and pharmacogenetic factors associated with irinotecan toxicity. Age, performance status, co-medication and elevated transaminases have been associated with increased risk of diarrhea or neutropenia. Also, elevated bilirubin levels, due to liver impairment, conjugation disorders or UGT1A1 *28 genotype, have been associated with increased incidence of grades 3 intestinal toxicity and neutropenia. UGT1A1 *28 homozygosity is strongly associated with irinotecan-induced neutropenia and polymorphisms in the transporting peptides ABCB1 and OATP1B1 have also been associated with gastrointestinal toxicity and irinotecan pharmacokinetics, respectively. In the irinotecan product label, it is advised to reduce the irinotecan starting dose for UGT1A1 *28 homozygotes. However, due to the lack of prospective data, it is yet unknown whether dose reduction leads to reduced toxicity or altered antitumor effect. Combined toxicity analysis reveals that most patients experiencing grade 3-4 diarrhea and/or neutropenia are not homozygous for UGT1A1 *28. Future studies should combine pharmacogenetics with clinical determinants such as performance status and co-medication as to predict irinotecan toxicity and to develop predefined dosing algorithms.
伊立替康是一种拓扑异构酶-I抑制剂，对实体瘤具有广泛的抗肿瘤活性。其使用可能导致严重毒性，主要是中性粒细胞减少和腹泻，这可能危及生命。本综述讨论了与伊立替康毒性相关的临床决定因素和药物遗传学因素。年龄、体能状态、合并用药和转氨酶升高与腹泻或中性粒细胞减少风险增加有关。此外，由于肝功能损害、结合障碍或UGT1A1 *28基因型导致的胆红素水平升高，与3级肠道毒性和中性粒细胞减少的发生率增加有关。UGT1A1 *28纯合性与伊立替康诱导的中性粒细胞减少密切相关，转运肽ABCB1和OATP1B1的多态性也分别与胃肠道毒性和伊立替康药代动力学有关。在伊立替康产品标签中，建议降低UGT1A1 *28纯合子的伊立替康起始剂量。然而，由于缺乏前瞻性数据，尚不清楚剂量降低是否会导致毒性降低或抗肿瘤效果改变。联合毒性分析显示，大多数发生3-4级腹泻和/或中性粒细胞减少的患者并非UGT1A1 *28纯合子。未来的研究应将药物遗传学与体能状态和合并用药等临床决定因素相结合，以预测伊立替康毒性并制定预定义的给药算法。
