Irinotecan-Induced Toxicity: A Pharmacogenetic Study Beyond UGT1A1

被引：8
作者：
de With, Mirjam [1 ,2 ]
van Doorn, Leni [1 ]
Kloet, Esmay [1 ]
van Veggel, Anne [2 ]
Matic, Maja [2 ]
de Neijs, Micha J. [1 ]
de Hoop, Esther [1 ]
van Meerten, Esther [1 ]
van Schaik, Ron H. N. [2 ]
Mathijssen, Ron H. J. [1 ]
Bins, Sander [1 ]
机构：
[1] Erasmus MC, Dept Med Oncol, Canc Inst, Dr Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands
[2] Erasmus MC, Dept Clin Chem, Dr Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands
来源：
CLINICAL PHARMACOKINETICS | 2023年 / 62卷 / 11期
关键词：
FLUOROURACIL FAILURE; ACTIVE METABOLITE; RANDOMIZED-TRIAL; ELDERLY-PATIENTS; CPT-11; SN-38; TUMOR; PHARMACOKINETICS; CARBOXYLESTERASE; POLYMORPHISMS;
D O I：
10.1007/s40262-023-01279-7
中图分类号：
R9 [药学];
学科分类号：
1007 ;
摘要：
Background and objective Side effects of irinotecan treatment can be dose limiting and may impair quality of life. In this study, we investigated the correlation between single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in the irinotecan metabolism and transport, outside UGT1A1, and irinotecan-related toxicity. We focused on carboxylesterases, which are involved in formation of the active metabolite SN-38 and on drug transporters. Methods Patients who provided written informed consent at the Erasmus Medical Center Cancer Institute to the Code Geno study (local protocol: MEC02-1002) or the IRI28-study (NTR-6612) were enrolled in the study and were genotyped for 15 SNPs in the genes CES1, CES2, SLCO1B1, ABCB1, ABCC2, and ABCG2. Results From 299 evaluable patients, 86 patients (28.8%) developed severe irinotecan-related toxicity. A significantly higher risk of toxicity was seen in ABCG2 c.421C> A variant allele carriers (P = 0.030, OR 1.88, 95% CI 1.06-3.34). Higher age was associated with all grade diarrhea (P = 0.041, OR 1.03, 95% CI 1.00-1.06). In addition, CES1 c.1165-41C>T and CES1 n.95346T>C variant allele carriers had a lower risk of all-grade thrombocytopenia (P = 0.024, OR 0.42, 95% CI 0.20-0.90 and P = 0.018, OR 0.23, 95% CI 0.08-0.79, respectively). Conclusion Our study indicates that ABCG2 and CES1 SNPs might be used as predictive markers for irinotecan-induced toxicity.
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收藏
页码：1589 / 1597
页数：9
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