Phase I and pharmacokinetic study of intravenous irinotecan plus oral ciclosporin in patients with fuorouracil-refractory metastatic colon cancer

• Published in: Journal of clinical oncology Vol. 21; no. 6; p. 1125
• Main Authors: Chester, John D, Joel, Simon P, Cheeseman, Susan L, Hall, Geoffrey D, Braun, Michael S, Perry, Jackie, Davis, Theresa, Button, Christopher J, Seymour, Matthew T
• Format: Journal Article
• Language: English
• Published: United States 15.03.2003
• Subjects: Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Colonic Neoplasms - blood; Colonic Neoplasms - drug therapy; Colonic Neoplasms - pathology; Cyclosporine - administration & dosage; Cyclosporine - pharmacology; Drug Resistance, Neoplasm; Female; Fluorouracil - pharmacology; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Staging; Treatment Outcome
• ISSN: 0732-183X

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. 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. 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. 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.