Phase I and Pharmacokinetic Study of Intravenous Irinotecan Plus Oral Ciclosporin in Patients With Fluorouracil-Refractory Metastatic Colon Cancer
| Autor: | John D. Chester, Jackie Perry, Simon P. Joel, Christopher J. Button, Susan L. Cheeseman, Matthew T. Seymour, Theresa Davis, Geoffrey D. Hall, Michael Braun |
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| Rok vydání: | 2003 |
| Předmět: |
Adult
Male Antimetabolites Antineoplastic Cancer Research medicine.medical_specialty medicine.medical_treatment Administration Oral Pharmacology Neutropenia Irinotecan Gastroenterology Pharmacokinetics Oral administration Internal medicine Antineoplastic Combined Chemotherapy Protocols Humans Medicine Infusions Intravenous Aged Neoplasm Staging Chemotherapy business.industry Area under the curve Middle Aged Ciclosporin medicine.disease Antineoplastic Agents Phytogenic Treatment Outcome Oncology Drug Resistance Neoplasm Fluorouracil Colonic Neoplasms Cyclosporine Camptothecin Female business medicine.drug |
| Zdroj: | Journal of Clinical Oncology. 21:1125-1132 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2003.08.049 |
| Popis: | Purpose: 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 and Methods: Patients with fluorouracil-refractory metastatic colorectal cancer received escalating doses of intravenous irinotecan from 40 to 125 mg/m2 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/m2. 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/m2 and area under the curve (AUC)0-tn was increased 2.2-fold by the coadministration of Cs. Similar significant increases in AUC0-24h 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. Conclusion: The maximum tolerated irinotecan dose and recommended dose for phase II studies is 100 mg/m2 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. |
| Databáze: | OpenAIRE |
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