title: Flat-fixed dosing of irinotecan: influence on pharmacokinetic and pharmacodynamic variability.
abstract: OBJECTIVE
  In a previous analysis, it was shown that body-surface area (BSA) is not a predictor of irinotecan pharmacokinetic parameters. Here, we prospectively evaluated the effects of administering a flat-fixed irinotecan dose to cancer patients, regardless of BSA.
  
  
  METHODS
  Twenty-six cancer patients (12 females) received a fixed irinotecan dose of 600 mg, given as a 90-min i.v. infusion. Plasma concentrations of irinotecan and its metabolites SN-38 (7-ethyl-10-hydroxycamptothecin) and SN-38G (SN-38 glucuronide) were measured during the first cycle and analyzed using nonlinear mixed-effect modeling. Data were compared with those obtained in 47 cancer patients (19 females) who received irinotecan at a BSA-normalized dose of 350 mg/m(2).
  
  
  RESULTS
  The interindividual variability in irinotecan clearance (25.9% versus 25.1%; P = 0.93), in relative extent of conversion to SN-38 (47.8% versus 42.7%; P = 0.24), and in relative extent of SN-38 glucuronidation (71.2% versus 72.4%; P = 0.95) were not significantly different between the two dose groups. Variance differences in irinotecan-mediated hematological side effects were also similar between the 600 mg and 350 mg/m(2) groups (P > 0.14).
  
  
  CONCLUSIONS
  These findings suggest that flat-fixed dosing of irinotecan does not result in increased pharmacokinetic/pharmacodynamic variability and could be safely used to supplant current dosing strategies based on BSA.
authors.affiliation: Department of Medical Oncology, Erasmus University MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: Floris A
authors.initials: FA
authors.lastname: de Jong
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: Rujia
authors.initials: R
authors.lastname: Xie
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D001830:Body Surface Area; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005965:Glucuronates / Q000493:pharmacokinetics; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D015233:Models, Statistical; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; D000972:Antineoplastic Agents, Phytogenic; D005965:Glucuronates; D000077146:Irinotecan; D002166:Camptothecin