title: Dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with cancer.
abstract: OBJECTIVE
  The risk of severe neutropenia from treatment with irinotecan is related in part to UGT1A1*28, a variant that reduces the elimination of SN-38, the active metabolite of irinotecan. We aimed to identify the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan in patients with advanced solid tumors stratified by the *1/*1, *1/*28, and *28/*28 genotypes.
  
  
  METHODS
  Sixty-eight patients received an intravenous flat dose of irinotecan every 3 weeks. Forty-six percent of the patients had the *1/*1 genotype, 41% had the *1/*28 genotype, and 13% had the *28/*28 genotype. The starting dose of irinotecan was 700 mg in patients with the *1/*1 and *1/*28 genotypes and 500 mg in patients with the *28/*28 genotype. Pharmacokinetic evaluation was performed at cycle 1.
  
  
  RESULTS
  In patients with the *1/*1 genotype, the MTD was 850 mg (four DLTs per 16 patients), and 1,000 mg was not tolerated (two DLTs per six patients). In patients with the *1/*28 genotype, the MTD was 700 mg (five DLTs per 22 patients), and 850 mg was not tolerated (four DLTs per six patients). In patients with the *28/*28 genotype, the MTD was 400 mg (one DLT per six patients), and 500 mg was not tolerated (three DLTs per three patients). The DLTs were mainly myelosuppression and diarrhea. Irinotecan clearance followed linear kinetics. At the MTD for each genotype, dosing by genotype resulted in similar SN-38 areas under the curve (AUCs; r(2) = 0.0003; P = .97), but the irinotecan AUC was correlated with the actual dose (r(2) = 0.39; P < .001). Four of 48 patients with disease known to be responsive to irinotecan achieved partial response.
  
  
  CONCLUSIONS
  The UGT1A1*28 genotype can be used to individualize dosing of irinotecan. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in patients receiving irinotecan.
authors: Federico Innocenti, Richard L. Schilsky, Jacqueline Ramírez, Linda Janisch, Samir Undevia, Larry K. House, Soma Das, Kehua Wu, Michelle Turcich, Theodore Karrison, Michael L. Maitland, Ravi Salgia, and Mark J. Ratain, University of Chicago, Chicago; and Robert Marsh, NorthShore University Health System, Evanston, IL. innocent@unc.edu.
authors: Federico
authors: F
authors: Innocenti
authors: Federico Innocenti, Richard L. Schilsky, Jacqueline Ramírez, Linda Janisch, Samir Undevia, Larry K. House, Soma Das, Kehua Wu, Michelle Turcich, Theodore Karrison, Michael L. Maitland, Ravi Salgia, and Mark J. Ratain, University of Chicago, Chicago; and Robert Marsh, NorthShore University Health System, Evanston, IL.
authors: Richard L
authors: RL
authors: Schilsky
authors: Federico Innocenti, Richard L. Schilsky, Jacqueline Ramírez, Linda Janisch, Samir Undevia, Larry K. House, Soma Das, Kehua Wu, Michelle Turcich, Theodore Karrison, Michael L. Maitland, Ravi Salgia, and Mark J. Ratain, University of Chicago, Chicago; and Robert Marsh, NorthShore University Health System, Evanston, IL.
authors: Jacqueline
authors: J
authors: Ramírez
authors: Federico Innocenti, Richard L. Schilsky, Jacqueline Ramírez, Linda Janisch, Samir Undevia, Larry K. House, Soma Das, Kehua Wu, Michelle Turcich, Theodore Karrison, Michael L. Maitland, Ravi Salgia, and Mark J. Ratain, University of Chicago, Chicago; and Robert Marsh, NorthShore University Health System, Evanston, IL.
authors: Linda
authors: L
authors: Janisch
authors: Federico Innocenti, Richard L. Schilsky, Jacqueline Ramírez, Linda Janisch, Samir Undevia, Larry K. House, Soma Das, Kehua Wu, Michelle Turcich, Theodore Karrison, Michael L. Maitland, Ravi Salgia, and Mark J. Ratain, University of Chicago, Chicago; and Robert Marsh, NorthShore University Health System, Evanston, IL.
authors: Samir
authors: S
authors: Undevia
authors: Federico Innocenti, Richard L. Schilsky, Jacqueline Ramírez, Linda Janisch, Samir Undevia, Larry K. House, Soma Das, Kehua Wu, Michelle Turcich, Theodore Karrison, Michael L. Maitland, Ravi Salgia, and Mark J. Ratain, University of Chicago, Chicago; and Robert Marsh, NorthShore University Health System, Evanston, IL.
authors: Larry K
authors: LK
authors: House
authors: Federico Innocenti, Richard L. Schilsky, Jacqueline Ramírez, Linda Janisch, Samir Undevia, Larry K. House, Soma Das, Kehua Wu, Michelle Turcich, Theodore Karrison, Michael L. Maitland, Ravi Salgia, and Mark J. Ratain, University of Chicago, Chicago; and Robert Marsh, NorthShore University Health System, Evanston, IL.
authors: Soma
authors: S
authors: Das
authors: Federico Innocenti, Richard L. Schilsky, Jacqueline Ramírez, Linda Janisch, Samir Undevia, Larry K. House, Soma Das, Kehua Wu, Michelle Turcich, Theodore Karrison, Michael L. Maitland, Ravi Salgia, and Mark J. Ratain, University of Chicago, Chicago; and Robert Marsh, NorthShore University Health System, Evanston, IL.
authors: Kehua
authors: K
authors: Wu
authors: Federico Innocenti, Richard L. Schilsky, Jacqueline Ramírez, Linda Janisch, Samir Undevia, Larry K. House, Soma Das, Kehua Wu, Michelle Turcich, Theodore Karrison, Michael L. Maitland, Ravi Salgia, and Mark J. Ratain, University of Chicago, Chicago; and Robert Marsh, NorthShore University Health System, Evanston, IL.
authors: Michelle
authors: M
authors: Turcich
authors: Federico Innocenti, Richard L. Schilsky, Jacqueline Ramírez, Linda Janisch, Samir Undevia, Larry K. House, Soma Das, Kehua Wu, Michelle Turcich, Theodore Karrison, Michael L. Maitland, Ravi Salgia, and Mark J. Ratain, University of Chicago, Chicago; and Robert Marsh, NorthShore University Health System, Evanston, IL.
authors: Robert
authors: R
authors: Marsh
authors: Federico Innocenti, Richard L. Schilsky, Jacqueline Ramírez, Linda Janisch, Samir Undevia, Larry K. House, Soma Das, Kehua Wu, Michelle Turcich, Theodore Karrison, Michael L. Maitland, Ravi Salgia, and Mark J. Ratain, University of Chicago, Chicago; and Robert Marsh, NorthShore University Health System, Evanston, IL.
authors: Theodore
authors: T
authors: Karrison
authors: Federico Innocenti, Richard L. Schilsky, Jacqueline Ramírez, Linda Janisch, Samir Undevia, Larry K. House, Soma Das, Kehua Wu, Michelle Turcich, Theodore Karrison, Michael L. Maitland, Ravi Salgia, and Mark J. Ratain, University of Chicago, Chicago; and Robert Marsh, NorthShore University Health System, Evanston, IL.
authors: Michael L
authors: ML
authors: Maitland
authors: Federico Innocenti, Richard L. Schilsky, Jacqueline Ramírez, Linda Janisch, Samir Undevia, Larry K. House, Soma Das, Kehua Wu, Michelle Turcich, Theodore Karrison, Michael L. Maitland, Ravi Salgia, and Mark J. Ratain, University of Chicago, Chicago; and Robert Marsh, NorthShore University Health System, Evanston, IL.
authors: Ravi
authors: R
authors: Salgia
authors: Federico Innocenti, Richard L. Schilsky, Jacqueline Ramírez, Linda Janisch, Samir Undevia, Larry K. House, Soma Das, Kehua Wu, Michelle Turcich, Theodore Karrison, Michael L. Maitland, Ravi Salgia, and Mark J. Ratain, University of Chicago, Chicago; and Robert Marsh, NorthShore University Health System, Evanston, IL.
authors: Mark J
authors: MJ
authors: Ratain
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme