Clinical Cancer Research Bridging the Lab and the Clinic in Cancer Medicine Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine
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Clinical Cancer Research Vol. 9, 625-632, February 2003
© 2003 American Association for Cancer Research

Clinical Trials

{alpha}1 Acid Glycoprotein Binds to Imatinib (STI571) and Substantially Alters Its Pharmacokinetics in Chronic Myeloid Leukemia Patients1

Carlo Gambacorti-Passerini2, Massimo Zucchetti, Domenico Russo, Roberta Frapolli, Magda Verga, Silvia Bungaro, Lucia Tornaghi, Fabio Rossi, Pietro Pioltelli, Enrico Pogliani, Daniele Alberti, Gianmarco Corneo and Maurizio D’Incalci

Department of Experimental Oncology, Istituto Nazionale Tumori, Milano, Italy [C. G-P., S. B., L. T.]; Department of Oncology, Mario Negri Institute for Pharmacological Research, Milano, Italy [M. Z., R. F., M. D.]; Section of Hematology, University of Milano Bicocca, S. Gerardo Hospital, Monza, Italy [C. G-P., M. V., S. B., L. T., F. R., P. P., E. P., G. C.]; Division of Hematology, University of Udine, Udine, Italy [D. R.]; and Oncology Business Unit, Novartis Italia, Origgio, Italy [D. A.]

Purpose: Imatinib (Glivec) is a potent inhibitor of bcr/abl, an oncogenic fusion protein that causes chronic myelogenous leukemia (CML). {alpha}1 acid glycoprotein (AGP) binds to imatinib with high affinity and inhibits imatinib activity in vitro and in vivo in an animal model. A pharmacokinetics analysis of imatinib was undertaken in CML patients.

Experimental Design: Imatinib plasma concentrations were measured in 19 CML patients treated with imatinib (400 or 600 mg/day). Five patients received a concomitant short-term course of clindamycin (CLI).

Results: A positive correlation between AGP and imatinib plasma levels was observed. CLI administration decreased imatinib plasma concentrations, evaluated as area under the curve (AUC) and peak concentrations (Cmax). The effects of a bolus of CLI was studied in three patients on imatinib 23 h after the last imatinib dose. Within 5–10 min in three of three cases, CLI caused a decrease in imatinib plasma concentrations of 2.6-, 2.7-, and 4.7-fold, respectively. In vitro experiments using fresh blasts from CML patients showed that AGP, at concentrations observed in the patients, decreased imatinib intracellular concentrations up to 10 times and blocked imatinib activity. The incubation with CLI restored imatinib intracellular concentrations and biological activity.

Conclusion: AGP exerts significant effects of the pharmacokinetics, plasma concentrations, and intracellular distribution of imatinib in CML patients; these data indicate that plasma imatinib levels represent unreliable indicators of the cellular concentrations of this molecule.




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Copyright © 2003 by the American Association for Cancer Research.