UGT1A1 genotype-specific phase I and pharmacokinetic study for combination chemotherapy with irinotecan and cisplatin: a Saitama tumor board study

Introduction: Genotyping of UGT1A1 could be useful for prediction of severe toxicities for patients treated with irinotecan; however, genotype-based recommended dose (RD) has not been established. The aim of the present study was to determine the RD of irinotecan in combination with cisplatin (CPT-P) for individuals with or without UGT1A1 polymorphisms. Materials and Methods: According to polymorphisms of UGT1A1*28, *6, and *27, RDs were determined by three-case cohort methods for patients with wild-type and heterotype, and by inter-patient dose escalation for homotype patients. Pharmacokinetic studies were also evaluated. During May 2009 and July 2011, 18 Japanese patients were enrolled; 16 patients with ovarian carcinoma, and two cases with cervical cancer. The RD of irinotecan was determined as 50 mg/m2 for the patients with wild-type, 40 mg/m2 for those with heterotype, and 30 mg/m2 for homotype UGT1A1 genotype. Results: Patients with homotype UGT1A1 alleles had a significantly lower glucuronidation ratio in comparison with UGT1A1 wild-type and heterotype cases. Conclusion: UGT1A1 genotype-based RDs of irinotecan in CPT-P therapy were determined. Further studies to investigate efficacy of the RD including response evaluation are needed to confirm the present results.

UDP-glucuronosyltransferase 1A1 (UGT1A1); UGT1A1*6; UGT1A1*28; Irinotecan; Cisplatin; Phase I.

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