TY - JOUR
T1 - Clinical pharmacokinetics of the new oral camptothecin gimatecan
T2 - The inter-patient variability is related to α1-acid glycoprotein plasma levels
AU - Frapolli, Roberta
AU - Zucchetti, Massimo
AU - Sessa, Cristiana
AU - Marsoni, Silvia
AU - Viganò, Lucia
AU - Locatelli, Alberta
AU - Rulli, Eliana
AU - Compagnoni, Anna
AU - Bello, Ezia
AU - Pisano, Claudio
AU - Carminati, Paolo
AU - D'Incalci, Maurizio
PY - 2010/2
Y1 - 2010/2
N2 - 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.
AB - 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.
KW - α-Acid glycoprotein
KW - Camptothecins
KW - Inter-patient variability
KW - Pharmacokinetics
KW - Statistical analysis
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U2 - 10.1016/j.ejca.2009.11.006
DO - 10.1016/j.ejca.2009.11.006
M3 - Article
C2 - 20007015
AN - SCOPUS:75449090831
VL - 46
SP - 505
EP - 516
JO - European Journal of Cancer
JF - European Journal of Cancer
SN - 0959-8049
IS - 3
ER -