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Impact of body-size measures on irinotecan clearance: alternative dosing recommendations
Ron H J Mathijssen1, Jaap Verweij, Maja J A de Jonge
1Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), 3008 AE Rotterdam, the Netherlands.
Purpose:
To evaluate relationships between various body-size measures and irinotecan (CPT-11) clearance and metabolism in cancer patients, and to provide future dosing recommendations for this agent.
Patients And Methods:
Pharmacokinetic data were obtained from 82 adult patients (50 men, 32 women; median age, 54 years) receiving CPT-11 as a 90-minute intravenous infusion (dose range, 175 to 350 mg/m(2)). In each patient, plasma samples were collected at timed intervals in the first administration of a 3-week schedule, and CPT-11 and its metabolite, SN-38, were measured by a liquid chromatographic assay.
Results:
The mean (+/- SD) CPT-11 clearance was 33.6 +/- 10.8 L/h, with an interindividual variability (IIV) of 32.1%. When clearance was adjusted for body-surface area (BSA), the IIV was similar (34.0%). In addition, in a multiple linear regression analysis, none of the studied measures (BSA, lean body mass, [adjusted] ideal body weight, and body mass index) was a significant covariate (P >.13; r(2) <.014) in our population. Similarly, BSA did not significantly contribute to variability in the relative extent of conversion to SN-38 (P =.26).
Conclusion:
BSA is not a predictor of CPT-11 clearance or SN-38 pharmacokinetics and does not contribute to reducing kinetic variability. These findings provide a rationale for the conduct of a comparative phase III study between BSA-based dosing and flat or fixed dosing of CPT-11.