Non-linear pharmacokinetics of irinotecan in mice.
Irinotecan (CPT-11) is a topoisomerase I inhibitor used in the treatment of metastatic colorectal cancer. Its conversion by carboxyl esterases is necessary to form the active metabolite SN-38. The aims of the study were to evaluate the linearity of CPT-11 pharmacokinetics and the influence of the schedule of administration of CPT-11 in mice, using a population pharmacokinetic approach with the NON-linear Mixed Effects Model (NONMEM) program. Mice were treated using two doses and two schedules of administration [10 mg/kg/day (dailyx5)x2 or 50 mg/kg/day on days 1 and 12]. Plasma concentrations of both CPT-11 and SN-38 were determined by HPLC. A pharmacokinetic model based on both immediate conversion of CPT-11 to SN-38 for a fraction of the administered dose and saturable process for the remaining fraction fitted the data well. Refinements of the model allowed us to evaluate both the impacts of the dose and the schedule of administration on the pharmacokinetic parameters. We conclude that the pharmacokinetics of CPT-11 is not linear in mice. Extrapolation of both pharmacokinetic and pharmacodynamic preclinical results to humans may be limited by species particularities for this drug.
Rouits
Elisabeth
E
Institut Claudius-Regaud, EA 3035, 20 rue du Pont-St-Pierre, 31052 Toulouse, France.
Guichard
Sylvie
S
Canal
Pierre
P
Chatelut
Etienne
E
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D000077146:Irinotecan; D051379:Mice; D008807:Mice, Inbred BALB C; D017711:Nonlinear Dynamics
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; D002166:Camptothecin