Clinical pharmacokinetics of the new oral camptothecin gimatecan: The inter-patient variability is related to α1-acid glycoprotein plasma levels

Roberta Frapolli, Massimo Zucchetti, Cristiana Sessa, Silvia Marsoni, Lucia Viganò, Alberta Locatelli, Eliana Rulli, Anna Compagnoni, Ezia Bello, Claudio Pisano, Paolo Carminati, Maurizio D'Incalci

Research output: Contribution to journalArticlepeer-review

Abstract

Aim of the study: To determine the pharmacokinetics of gimatecan, a camptothecin with a lipophilic substitution in position 7, given orally to patients participating in the phase I study. Methods: Pharmacokinetics was evaluated in 78 patients after oral daily dose for 5 days a week for 1, 2 or 3 weeks by HPLC with a fluorescence detector. Results: Gimatecan was mainly present in plasma as lactone (>85%), the active form as DNA-topoisomerase I poison. The AUC0-24 on the first day of treatment normalised per daily dose (mg/m2), ranged from 194 to 2909 ng h/mL/mg/m2. The half-life was 77.1 ± 29.6 h, consequently Cmax and AUC rose 3-6-fold after multiple dosing. Multivariate analysis indicated the daily dose (p <0.0001) and the α1-acid glycoprotein (AGP) plasma levels (p <0.0001) as main predictors of gimatecan AUC0-24. In the overall analysis, daily dose and AGP plasma levels explained 85% of the deviance. The hydroxy metabolite ST1698 was present in plasma at low levels with AUC values of 5-15% of gimatecan. In mice, orally treated with gimatecan, plasma and tissue levels were 2-fold higher after treatment with a pro-inflammatory agent causing AGP induction. Conclusions: Gimatecan is orally absorbed and its variable plasma levels seem to be related to AGP plasma concentrations. Data obtained in mice, together with the fact that AGP levels largely exceeded gimatecan plasma concentrations, suggest that the increased gimatecan levels in patients with high AGP levels are not related to the binding of the drug to AGP with consequent reduced tissue drug distribution, but possibly to other mechanism associated with inflammation being AGP simply a marker of the inflammation process.

Original languageEnglish
Pages (from-to)505-516
Number of pages12
JournalEuropean Journal of Cancer
Volume46
Issue number3
DOIs
Publication statusPublished - Feb 2010

Keywords

  • α-Acid glycoprotein
  • Camptothecins
  • Inter-patient variability
  • Pharmacokinetics
  • Statistical analysis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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