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

Cancer Chemother Pharmacol. 2009 Feb;63(3):517-24. doi: 10.1007/s00280-008-0769-8. Epub 2008 May 22.

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/m(2). 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Area Under Curve
  • Brain Neoplasms / metabolism*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacokinetics
  • Enterohepatic Circulation*
  • Female
  • Glioma / metabolism*
  • Half-Life
  • Humans
  • Irinotecan
  • Male

Substances

  • Antineoplastic Agents, Phytogenic
  • Irinotecan
  • Camptothecin