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.

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/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.

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/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 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.

• Authors: 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
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 71 Issue 6 Pg. 1609-17 (Jun 2013) ISSN: 1432-0843 [Electronic] Germany
• PMID: 23595344 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Deoxycytidine
• Capecitabine
• Irinotecan
• UGT1A1 enzyme
• Glucuronosyltransferase
• Fluorouracil
• Camptothecin

Topics

• Adolescent
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Camptothecin (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Capecitabine
• Colorectal Neoplasms (drug therapy, genetics, pathology)
• Deoxycytidine (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Fluorouracil (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Glucuronosyltransferase (genetics)
• Humans
• Infusions, Intravenous
• Irinotecan
• Kaplan-Meier Estimate
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Metastasis
• Republic of Korea
• Young Adult