title: Phase I dose-finding and pharmacokinetic trial of irinotecan (CPT-11) administered every two weeks.
abstract: OBJECTIVE
  This trial was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic profile of irinotecan (CPT-11) when administered on a once-every-2-week schedule.
  
  
  METHODS
  CPT-11 was administered to successive cohorts of patients at progressively increasing starting doses ranging from 125 to 350 mg/m2. The MTD and DLTs were determined both for CPT-11 alone and for CPT-11 followed by filgrastim (G-CSF). Plasma samples were obtained during the first 24 hours after initial dosing to determine the total concentrations (lactone + carboxylate forms) of CPT-11; of the active metabolite SN-38; and of SN-38 glucuronide (SN-38G).
  
  
  RESULTS
  Neutropenic fever was the DLT for CPT-11 at the 300 mg/m2 dose level. When G-CSF was added, dose escalation beyond 350 mg/m2 could not be achieved due to grade 2-3 toxicities that prevented on-time retreatment with CPT-11. Severe, late diarrhea was uncommon on this schedule. Peak plasma concentrations of SN-38 and SN-38G were approximately 2.5% and 4.2% of the corresponding peak plasma concentration for CPT-II, respectively The harmonic mean terminal half-lives for CPT-11, SN-38, and SN-38G were 7.1 hours, 13.4 hours, and 12.7 hours, respectively. No predictive correlation was observed between CPT-11 or SN-38 peak concentration or AUC and first-cycle diarrhea, neutropenia, nausea, or vomiting. Across the range of doses studied, mean CPT-11 clearance was 14.0 +/- 4.0 l/h/m2 and volume of distribution was 146 +/- 45.9 l/m2.
  
  
  CONCLUSIONS
  When administered every two weeks, the recommended phase II starting dose of CPT-11 is 250 mg/m2 when given alone and 300 mg/m2 when supported by G-CSF. This every-two-week regimen offers a tolerable and active alternative to weekly or every-three-week single-agent CPT-11 therapy.
authors.affiliation: The University of Texas Health Science Center San Antonio, USA. mace.rothenberg@mcmail.vanderbilt.edu
authors.forename: M L
authors.initials: ML
authors.lastname: Rothenberg
authors.forename: J G
authors.initials: JG
authors.lastname: Kuhn
authors.forename: L J
authors.initials: LJ
authors.lastname: Schaaf
authors.forename: G I
authors.initials: GI
authors.lastname: Rodriguez
authors.forename: S G
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: M A
authors.initials: MA
authors.lastname: Villalona-Calero
authors.forename: D A
authors.initials: DA
authors.lastname: Rinaldi
authors.forename: L A
authors.initials: LA
authors.lastname: Hammond
authors.forename: S
authors.initials: S
authors.lastname: Hodges
authors.forename: A
authors.initials: A
authors.lastname: Sharma
authors.forename: G L
authors.initials: GL
authors.lastname: Elfring
authors.forename: R G
authors.initials: RG
authors.lastname: Petit
authors.forename: P K
authors.initials: PK
authors.lastname: Locker
authors.forename: L L
authors.initials: LL
authors.lastname: Miller
authors.forename: D D
authors.initials: DD
authors.lastname: von Hoff
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016179:Granulocyte Colony-Stimulating Factor; D000077146:Irinotecan; D002166:Camptothecin