title: UGT1A1 promoter genotype correlates with SN-38 pharmacokinetics, but not severe toxicity in patients receiving low-dose irinotecan.
abstract: OBJECTIVE
  To study the association between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity as well as irinotecan disposition in pediatric patients with solid tumors receiving low-dose, protracted irinotecan (15 to 75 mg/m2 daily for 5 days for 2 consecutive weeks).
  
  
  METHODS
  Seventy-four patients on five institutional clinical trials received irinotecan (15 to 75 mg/m2) daily intravenously or orally for 5 days for 2 consecutive weeks. Genomic DNA was genotyped for UGT1A1*28, and patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the UGT1A1 promoter region. Patients were evaluated for gastrointestinal and hematologic toxicity, as well as baseline and maximal serum bilirubin levels. Toxicity and pharmacokinetic results were evaluated during courses 1 and 2 of irinotecan therapy.
  
  
  RESULTS
  The frequencies of 6/6, 6/7, and 7/7 genotypes were 27 (36.5%), 36 (48.6%), and 9 (12.2%) of 74 patients, respectively. Patients with 7/7 genotype had a statistically greater baseline total bilirubin than patients with 6/6 or 6/7 genotype (P = .005). UGT1A1*28 genotype was not associated with grade 3 and 4 neutropenia (P = .21 for course 1; P = .23 for course 2) or diarrhea (P = .176 for course 1; P = .87 for course 2). However, patients with the 7/7 genotype tended to have higher SN-38 area under the plasma time-concentration curve (AUC) values and lower SN-38G/SN-38 AUC ratios.
  
  
  CONCLUSIONS
  Severe toxicity was not increased in pediatric patients with the 7/7 genotype when treated with a low-dose protracted schedule of irinotecan. Therefore, UGT1A1 genotyping is not a useful prognostic indicator of severe toxicity for patients treated with this irinotecan dosage and schedule.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA. clinton.stewart@stjude.org
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Melinda A
authors.initials: MA
authors.lastname: O'Shaughnessy
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Throm
authors.forename: Charles H
authors.initials: CH
authors.lastname: Fraga
authors.forename: Thandranese
authors.initials: T
authors.lastname: Owens
authors.forename: Tiebin
authors.initials: T
authors.lastname: Liu
authors.forename: Catherine
authors.initials: C
authors.lastname: Billups
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Galindo
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Furman
authors.forename: Lisa M
authors.initials: LM
authors.lastname: McGregor
mesh_terms: D000293:Adolescent; D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D009364:Neoplasm Recurrence, Local; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D004273:DNA, Neoplasm; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme