Objectives: Our objective was to build population pharmacokinetic models that describe plasma concentrations of irinotecan (CPT-11) and its metabolites 7-ethyl-10-hydroxycamptothecin (SN-38) and SN-38 glucuronide (SN-38G) and to investigate the pharmacokinetic-pharmacodynamic relationships between drug exposure and diarrhea, the major dose-limiting toxicity. Methods: Data were obtained from 109 patients (65 men and 44 women) who received 1.5-hour (range, 0.75- to 2.25-hour) intravenous infusions of irinotecan at doses that ranged from 100 to 350 mg/m2; 44 patients had a second course. The population pharmacokinetic models were developed to describe plasma concentration-time profiles. The area under the concentration-time curve from time zero to 60 hours [AUC (0-60)] was used as a measure of drug exposure to model the probabilities of diarrhea with use of a logistic regression model. Results: A 3-compartment pharmacokinetic model best described the disposition of irinotecan, whereas SN-38 and SN-38G showed 2-compartmental characteristics. The population estimate of clearance for irinotecan was 31.6 L/h, and the volume of distribution at steady-state (Vss) was 263 L. The clearance divided by formation fraction (Fm) was 712 L/h and 66.8 L/h for SN-38 and SN-38G, respectively. The Vss/Fm was 72,000 L for SN-38 and 85.4 L for SN-38G. The frequencies of diarrhea scores in this study were 46% (grade 0), 28% (grade 1), 20% (grade 2), 4% (grade 3), and 2% (grade 4). Significant correlations between AUC(0-60) and diarrhea scores were found for irinotecan (P < .05) and SN-38G (P < .01) but not for SN-38 or the biliary index. Conclusions: In this population analysis, irinotecan and SN-38G AUC values were appropriate predictors of the risk for diarrhea, and SN-38G AUC showed the stronger relationship of the two. The developed population models may be useful in further clinical development of this agent.

doi.org/10.1067/mcp.2002.126741, hdl.handle.net/1765/57911
Clinical Pharmacology and Therapeutics
Department of Medical Oncology

Xie, R., Mathijssen, R., Sparreboom, A., Verweij, J., & Karlsson, M. O. (2002). Clinical pharmacokinetics of irinotecan and its metabolites in relation with diarrhea. Clinical Pharmacology and Therapeutics, 72(3), 265–275. doi:10.1067/mcp.2002.126741