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Pharmacokinetics and Pharmacodynamics of Imatinib in a Phase I Trial With Chronic Myeloid Leukemia Patients

From Novartis Pharma AG, Basel, Switzerland; Department of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR; The University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Department of Hematology-Oncology, University of California Los Angeles, Los Angeles, CA

Address reprint requests to Bin Peng, MD, PhD, Clinical Pharmacology, Novartis, One Health Plaza, Building 419, Room 2368, East Hanover, NJ 07936-1080; e-mail: bin.peng{at}pharma.novartis.com

PURPOSE: To evaluate the basic pharmacokinetic (PK) characteristics of imatinib mesylate and assess the relationship between the PK and pharmacodynamic (PD) properties of the drug.

PATIENTS AND METHODS: The PK and PD properties of imatinib were investigated during a phase I trial that included 64 adult patients with Philadelphia chromosome–positive leukemias. Patients received imatinib orally once or twice daily. PK parameters of imatinib, derived from the plasma concentration–time curves, were determined. PD response, defined as the WBC after 1 month of treatment with imatinib, was used to develop an efficacy model. A maximum inhibition–effect model was used to describe the relationship between reduction in WBC and drug exposure parameters.

RESULTS: Imatinib exposure was dose proportional after oral administration for the dose range of 25 to 1,000 mg. There was a 1.5- to three-fold drug accumulation after repeated once-daily dosing. Mean plasma trough concentration was 0.57 µg/mL (approximately 1 µmol/L) 24 hours after administration of 350 mg of imatinib at steady-state, which exceeds the 50% inhibitory concentration required to inhibit proliferation of Bcr-Abl–positive leukemic cells. Analysis of PK/PD relationships indicates that the initial hematologic response depends on the administered dose for patients with chronic myeloid leukemia.

CONCLUSION: Drug exposure (area under the concentration-time curve) is dose proportional for the dose range of 25 to 1,000 mg, and there is a 1.5- to three-fold drug accumulation at steady-state after once-daily dosing. Analysis of the relationship between PD (WBC reduction) and PK parameters at steady-state indicates that a dose of 400 mg or greater is required for maximal PD effect.

Presented in part at the American Society of Clinical Oncology Annual Meeting, Orlando, FL, May 18-21, 2001, and the American Society of Clinical Oncology Online Molecular Oncology Grand Rounds Virtual Symposium.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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