A UGT1A1*28 and*6 genotype-directed phase I dose-escalation trial of irinotecan with fixed-dose capecitabine in Korean patients with metastatic colorectal cancer

作者：Kim Kyu pyo; Kim Ho Sook; Sym Sun Jin; Bae Kyun Seop; Hong Yong Sang; Chang Heung Moon; Lee Jae Lyun; Kang Yoon Koo; Lee Jung Shin; Shin Jae Gook; Kim Tae Won^*

来源：Cancer Chemotherapy and Pharmacology, 2013, 71(6): 1609-1617.

DOI：10.1007/s00280-013-2161-6

• UGT1A1
• Polymorphism
• Irinotecan
• Capecitabine
• Colorectal

UGT1A1 genotypes are important when considering treatment with irinotecan-containing regimens. In this study, we determined the dose, efficacy, and tolerability of irinotecan according to UGT1A1 genotypes when combined with capecitabine in patients with metastatic colorectal cancer. %26lt;br%26gt;Patients with histologically confirmed metastatic adenocarcinoma of the colon or rectum were enrolled into a UGT1A1 genotype-directed dose-escalation trial of irinotecan plus fixed-dose capecitabine (2,000 mg/m(2)/day). The starting dose of irinotecan was different for each genotype group and ranged from 200 to 280 mg/m(2). Pharmacokinetic concentrations of irinotecan and metabolites were determined by LC/MS/MS. %26lt;br%26gt;Fifty patients were genotyped for UGT1A1 *28 and *6, and grouped according to the numbers of defective alleles (DA): 0, 1, and 2. Plasma concentrations of irinotecan, SN-38, and SN-38G were measured. The maximum tolerated dose of irinotecan was 350 mg/m(2) for the 0 and 1 DA groups, and 200 mg/m(2) for the 2 DA group. For the 0, 1, and 2 DA groups, mean AUC(last) ratios of SN-38G to SN-38 were 7.72, 5.71, and 2.72 (P = 0.0023) and relative dose intensities at recommended dose were 85, 83, and 97 %. %26lt;br%26gt;Irinotecan dosing based on UGT1A1*28 and *6 is feasible, and higher doses of irinotecan can be safely administered in patients with 0 or 1 DA, compared to those with 2 DA.

• 出版日期2013-6