Enterohepatic recirculation model of irinotecan (CPT-11) and metabolite pharmacokinetics in patients with glioma |
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Authors: | Islam R. Younis Samuel Malone Henry S. Friedman Larry J. Schaaf William P. Petros |
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Affiliation: | (1) Department of Basic Pharmaceutical Sciences and Mary Babb Randolph Cancer Center, West Virginia University Health Sciences Center, P.O. Box 9300, Morgantown, WV 26506, USA;(2) Duke University Medical Center, Durham, NC, USA;(3) Department of Surgery, Duke University Medical Center, Durham, NC, USA;(4) The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA |
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Abstract: | Background Enterohepatic recirculation of irinotecan and one of its metabolites, SN-38, has been observed in pharmacokinetic data sets from previous studies. A mathematical model that can incorporate this phenomenon was developed to describe the pharmacokinetics of irinotecan and its metabolites. Patients and methods A total of 32 patients with recurrent malignant glioma were treated with weekly intravenous administration of irinotecan at a dose of 125 mg/m2. Plasma concentrations of irinotecan and its three major metabolites were determined. Pharmacokinetic models were developed and tested for simultaneous fit of parent drug and metabolites, including a recirculation component. Results Rebound in the plasma concentration suggestive of enterohepatic recirculation at approximately 0.5–1 h post-infusion was observed in most irinotecan plasma concentration profiles, and in some plasma profiles of the SN-38 metabolite. A multi-compartment model containing a recirculation chain was developed to describe this process. The recirculation model was optimal in 22 of the 32 patients compared to the traditional model without the recirculation component. Conclusion A recirculation chain incorporated in a multi-compartment pharmacokinetic model of irinotecan and its metabolites appears to improve characterization of this drug’s disposition in patients with glioma. |
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Keywords: | Irinotecan Pharmacokinetics Enterohepatic recirculation |
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