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Enterohepatic recirculation model of irinotecan (CPT-11) and metabolite pharmacokinetics in patients with glioma

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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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Acknowledgments

This paper is supported in part by the Mylan Chair of Pharmacology at West Virginia University.

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Authors and Affiliations

  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

    Islam R. Younis & William P. Petros

  2. Duke University Medical Center, Durham, NC, USA

    Samuel Malone & Henry S. Friedman

  3. Department of Surgery, Duke University Medical Center, Durham, NC, USA

    Henry S. Friedman

  4. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    Larry J. Schaaf

Authors
  1. Islam R. Younis
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  2. Samuel Malone
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  3. Henry S. Friedman
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  4. Larry J. Schaaf
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  5. William P. Petros
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Correspondence to William P. Petros.

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Younis, I.R., Malone, S., Friedman, H.S. et al. Enterohepatic recirculation model of irinotecan (CPT-11) and metabolite pharmacokinetics in patients with glioma. Cancer Chemother Pharmacol 63, 517–524 (2009). https://doi.org/10.1007/s00280-008-0769-8

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  • DOI: https://doi.org/10.1007/s00280-008-0769-8

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