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

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 AUC_0-24 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 C_max 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 AUC_0-24. 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.