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
| Autor: | Kyu-Pyo Kim, Jae-Gook Shin, Tae Won Kim, Jae-Lyun Lee, Ho-Sook Kim, Jung Shin Lee, Sun Jin Sym, Yong Sang Hong, Yoon-Koo Kang, Kyun-Seop Bae, Heung-Moon Chang |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Oncology Cancer Research Colorectal cancer Kaplan-Meier Estimate Toxicology Deoxycytidine Antineoplastic Combined Chemotherapy Protocols Genotype Dose escalation Pharmacology (medical) Glucuronosyltransferase Neoplasm Metastasis Young adult Infusions Intravenous Middle Aged Tolerability Female Fluorouracil Colorectal Neoplasms therapeutics medicine.drug Adult medicine.medical_specialty Adolescent Maximum Tolerated Dose Irinotecan digestive system Fixed dose Disease-Free Survival Drug Administration Schedule Capecitabine Young Adult Internal medicine Republic of Korea medicine Humans neoplasms Aged Pharmacology Dose-Response Relationship Drug business.industry medicine.disease digestive system diseases stomatognathic diseases Camptothecin business |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 71:1609-1617 |
| ISSN: | 1432-0843 0344-5704 |
| Popis: | 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.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.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 %.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. |
| Databáze: | OpenAIRE |
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