PURPOSE: In a previous analysis, it was shown that body-surface area (BSA) is not a predictor of irinotecan pharmacokinetic parameters. Here, we prospectively evaluated the effects of administering a flat-fixed irinotecan dose to cancer patients, regardless of BSA. EXPERIMENTAL DESIGN: Twenty-six cancer patients (12 females) received a fixed irinotecan dose of 600 mg, given as a 90-min i.v. infusion. Plasma concentrations of irinotecan and its metabolites SN-38 (7-ethyl-10-hydroxycamptothecin) and SN-38G (SN-38 glucuronide) were measured during the first cycle and analyzed using nonlinear mixed-effect modeling. Data were compared with those obtained in 47 cancer patients (19 females) who received irinotecan at a BSA-normalized dose of 350 mg/m(2). RESULTS: The interindividual variability in irinotecan clearance (25.9% versus 25.1%; P = 0.93), in relative extent of conversion to SN-38 (47.8% versus 42.7%; P = 0.24), and in relative extent of SN-38 glucuronidation (71.2% versus 72.4%; P = 0.95) were not significantly different between the two dose groups. Variance differences in irinotecan-mediated hematological side effects were also similar between the 600 mg and 350 mg/m(2) groups (P > 0.14). CONCLUSIONS: These findings suggest that flat-fixed dosing of irinotecan does not result in increased pharmacokinetic/pharmacodynamic variability and could be safely used to supplant current dosing strategies based on BSA.

Adult, Aged, Antineoplastic Agents, Phytogenic/administration & dosage/pharmacokinetics, Area Under Curve, Body Surface Area, Camptothecin/*administration & dosage/*analogs & derivatives/*pharmacokinetics, Dose-Response Relationship, Drug, Female, Glucuronates/pharmacokinetics, Humans, Male, Metabolic Clearance Rate, Middle aged, Models, Statistical, Neoplasms/*drug therapy, Research Support, Non-U.S. Gov't
dx.doi.org/10.1158/1078-0432.CCR-03-0591, hdl.handle.net/1765/13428
Clinical Cancer Research
Erasmus MC: University Medical Center Rotterdam

de Jong, F.A, Mathijssen, A.H.J, Xie, R, Verweij, J, & Sparreboom, A. (2004). Flat-fixed dosing of irinotecan: influence on pharmacokinetic and pharmacodynamic variability. Clinical Cancer Research, 10(12 I), 4068–4071. doi:10.1158/1078-0432.CCR-03-0591