title: 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: OBJECTIVE
  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 %.
  
  
  CONCLUSIONS
  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.affiliation: Division of Oncology, Department of Medicine, Asan Medical Center, University of Ulsan College of Medicine, 86 Asanbyeongwon-gil, Songpa-ku, Seoul 138-736, Korea.
authors.forename: Kyu-pyo
authors.initials: KP
authors.lastname: Kim
authors.forename: Ho-Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Sun Jin
authors.initials: SJ
authors.lastname: Sym
authors.forename: Kyun Seop
authors.initials: KS
authors.lastname: Bae
authors.forename: Yong Sang
authors.initials: YS
authors.lastname: Hong
authors.forename: Heung-Moon
authors.initials: HM
authors.lastname: Chang
authors.forename: Jae Lyun
authors.initials: JL
authors.lastname: Lee
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
authors.forename: Jung Shin
authors.initials: JS
authors.lastname: Lee
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D056910:Republic of Korea; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme