Erschienen in:
01.06.2013 | Original Article
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
verfasst von:
Kyu-pyo Kim, Ho-Sook Kim, Sun Jin Sym, Kyun Seop Bae, Yong Sang Hong, Heung-Moon Chang, Jae Lyun Lee, Yoon-Koo Kang, Jung Shin Lee, Jae-Gook Shin, Tae Won Kim
Erschienen in:
Cancer Chemotherapy and Pharmacology
|
Ausgabe 6/2013
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Abstract
Purpose
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.
Methods
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/m2/day). The starting dose of irinotecan was different for each genotype group and ranged from 200 to 280 mg/m2. Pharmacokinetic concentrations of irinotecan and metabolites were determined by LC/MS/MS.
Results
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/m2 for the 0 and 1 DA groups, and 200 mg/m2 for the 2 DA group. For the 0, 1, and 2 DA groups, mean AUClast 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 %.
Conclusion
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.