(Cancer Sci 2010; 101: 722–727)
Although individuals carrying the UGT1A1 allele *28 have an increased risk of severe toxicities associated with irinotecan, no phase I study has been conducted based on the polymorphism. This report presents the recommended doses of irinotecan for patients with the respective genotypes. Twenty‐seven patients with advanced colorectal cancer were enrolled in this study, and the UGT1A1*28 polymorphism was genotyped before chemotherapy. One course of chemotherapy consisted of irinotecan infused once every 2 weeks at 70, 100, 120, and 150 mg/m2 at dose levels 1, 2, 3, and 4, respectively, and doxifluridine was administered orally. This treatment continued for at least 12 weeks. The dose‐limiting toxicity was determined as grade 3 hematological and non‐hematological toxicities for the TA6/TA6 (6/6) and TA6/TA7 (6/7) genotypes. The pharmacokinetics of irinotecan, SN‐38, and SN‐38 glucuronide, was assessed at dose level 2. Eighteen and nine patients had the 6/6 and 6/7 genotypes, respectively. The maximum tolerated dose (MTD) was not observed up to dose level 4 in patients with the 6/6 genotype. In contrast, MTD was observed at dose level 2 (100 mg/m2) in patients with the 6/7 genotype. Patients with the 6/7 genotype had a significantly higher area under the plasma time–concentration curve 0‐∞ SN‐38 (P = 0.022) and biliary index (P = 0.030) than those with 6/6. The recommended starting doses of biweekly irinotecan for phase II/III were 150 mg/m2 for patients with the UGT1A1 6/6 genotype and 70 mg/m2 for those with the 6/7 genotype, respectively. The gene polymorphism should be considered when determining the precise recommended doses to be administered in phase I studies.