Research article

Impact of imatinib on the pharmacokinetics and in vivo efficacy of etoposide and/or ifosfamide

Keyvan Rezaï¹ , François Lokiec¹ , Isabelle Grandjean² , Sophie Weill¹ , Patricia de Cremoux³ , Vincent Bordier² , Richard Ekue² , Mickael Garcia² , Marie-France Poupon⁵ and Didier Decaudin^4,6

¹Department of Pharmacology Oncology, Centre René Huguenin, Saint-Cloud, France

²Unit of Animal experiments, Research Section, Institut Curie, Paris, France

³Department of tumor Biology, Institut Curie, Paris, France

⁴Department of Clinical Hematology, Institut Curie, Paris, France

⁵FRE 2584, Section de Recherche, Institut Curie, Paris, France

⁶UMR144 CNRS/Institut Curie, Paris, France

author email corresponding author email

BMC Pharmacology 2007, 7:13doi:10.1186/1471-2210-7-13

Published:	27 October 2007

Abstract

Background

Using a human small cell lung cancer (SCLC) xenografted in nude mice, we have previously reported enhanced tumor growth inhibition following chemotherapy in combination with imatinib (STI571). We therefore investigated the in vivo impact of imatinib on the pharmacokinetics and efficacy of chemotherapy.

Methods

Two different human tumors were used: SCLC6 small cell lung cancer xenografted in nude mice, and LY-3 EBV-associated human B-cell lymphoma xenografted in SCID mice. Plasma, urine, and fecal concentrations of etoposide (VP16) were determined by a validated high performance liquid chromatography method. Plasma concentrations of ifosfamidewere determined by a validated gas chromatography assay with nitrogen-phosphorus detection.

Results

Slight tumor growth inhibition was induced by imatinib administered alone in one in vivo EBV-associated B-cell lymphomatous xenograft. In contrast, an increase of the chemotherapy-induced antitumor effect was observed in the lymphoma model but not in a small cell lung cancer model when mice bearing human xenografted tumors were treated concomitantly by imatinib and chemotherapy. This antitumor effect was not influenced by concomitant administration of fluconazole. The AUC0-3 h (Area Under the concentration-time Curve) of etoposide was increased when mice were treated with etoposide + imatinib due to decreased fecal excretion. In contrast, imatinib did not appear to influence the urinary excretion of etoposide, and concomitant administration of the CYP3A4 inhibitor, fluconazole, with imatinib did not modify the pharmacokinetics of etoposide plus imatinib alone.

Conclusion

Altogether, these results therefore justify further prospective phase I and II clinical trials with combinations of etoposide-based chemotherapy and imatinib in patients with certain cancers, such as malignant lymphoma, with careful toxicologic monitoring.