title: Phase I and pharmacokinetic study of intravenous irinotecan plus oral ciclosporin in patients with fuorouracil-refractory metastatic colon cancer.
abstract: OBJECTIVE
  To assess the safety and toxicity profile of escalating doses of intravenous irinotecan, in combination with a fixed dose of oral ciclosporin (Cs) and to determine the pharmacokinetic profile of irinotecan and its metabolites.
  
  
  METHODS
  Patients with fluorouracil-refractory metastatic colorectal cancer received escalating doses of intravenous irinotecan from 40 to 125 mg/m(2) every 2 weeks in combination with a fixed dose of oral Cs (5 mg/kg bid for 3 days). Pharmacokinetic analysis of plasma irinotecan and its metabolites SN38 and SN38G was performed during paired cycles with and without Cs.
  
  
  RESULTS
  Thirty-seven patients were treated. Dose-limiting toxicity of grade 4 neutropenia was seen at an irinotecan dose of 125 mg/m(2). There was no grade 4 diarrhea, and only one patient experienced grade 3 diarrhea. Toxicities caused by Cs were generally mild. Pharmacokinetic studies demonstrated that irinotecan clearance was reduced from 13.4 to 5.8 L/h/m(2) and area under the curve (AUC)(0-tn) was increased 2.2-fold by the coadministration of Cs. Similar significant increases in AUC(0-24h) were seen for both SN38 and SN38G (2.2-fold and 2.3-fold, respectively) in the presence of Cs. Antitumor activity was seen at every irinotecan dose level.
  
  
  CONCLUSIONS
  The maximum tolerated irinotecan dose and recommended dose for phase II studies is 100 mg/m(2) every 2 weeks. Dose-limiting diarrhea was not seen during this study, supporting the hypothesis that pharmacokinetic modulation of irinotecan by Cs may improve its therapeutic index. Further studies using this combination are warranted.
authors.affiliation: Cancer Research UK Clinical Centre at Leeds, Cookridge Hospital, Leeds LS16 6QB, United Kingdom.
authors.forename: John D
authors.initials: JD
authors.lastname: Chester
authors.forename: Simon P
authors.initials: SP
authors.lastname: Joel
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cheeseman
authors.forename: Geoffrey D
authors.initials: GD
authors.lastname: Hall
authors.forename: Michael S
authors.initials: MS
authors.lastname: Braun
authors.forename: Jackie
authors.initials: J
authors.lastname: Perry
authors.forename: Theresa
authors.initials: T
authors.lastname: Davis
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Button
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Seymour
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003110:Colonic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D016572:Cyclosporine; D005472:Fluorouracil; D002166:Camptothecin