title: A phase I trial of pharmacologic modulation of irinotecan with cyclosporine and phenobarbital.
abstract: The anticancer agent irinotecan has been demonstrated to improve the survival rate in patients with metastatic colorectal cancer. Its usage has been limited by severe toxicity. To modulate irinotecan pharmacokinetics and reduce the prevalence of severe toxicity, patients were treated with cyclosporine (INN, ciclosporin) and the irinotecan dose was increased from 25 to 72 mg/m2 weekly. Phenobarbital was then added, allowing dose escalation to 144 mg/m2. Dose-limiting toxicities were neutropenia and diarrhea. Irinotecan was well tolerated at the recommended phase II dose of 120 mg/m2, with a 6% prevalence of grade 4 neutropenia and an 18% prevalence of grade 3 diarrhea. Cyclosporine increased 7-ethyl-10-hydroxycamptothecin (SN-38) area under the concentration-time curve (AUC) by 23% to 630% and reduced irinotecan clearance by 39% to 64% when compared with historical controls. Phenobarbital increased irinotecan clearance by 27% (P < or =.001) and reduced SN-38 AUC by 75% (P < or =.001) when compared with patients treated with cyclosporine alone. Five partial responses were observed. Pharmacokinetic modulation of irinotecan with cyclosporine and phenobarbital has been demonstrated; further studies are necessary to evaluate whether this strategy improves the therapeutic index.
authors.affiliation: Department of Medicine, Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, IL 60637, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Innocenti
authors.forename: Samir D
authors.initials: SD
authors.lastname: Undevia
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramírez
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
authors.forename: Richard L
authors.initials: RL
authors.lastname: Schilsky
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: Marisol
authors.initials: M
authors.lastname: Prado
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D023381:Endpoint Determination; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000077146:Irinotecan; D008223:Lymphoma / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy*; D010634:Phenobarbital / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D006993:Hypnotics and Sedatives; D007166:Immunosuppressive Agents; D000077146:Irinotecan; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016572:Cyclosporine; D002166:Camptothecin; D010634:Phenobarbital