Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients

Bin Peng, Michael Hayes, Debra Resta, Amy Racine-Poon, Brian J. Druker, Moshe Talpaz, Charles L. Sawyers, Marianne Rosamilia, John Ford, Peter Lloyd, Renaud Capdeville

Research output: Contribution to journalArticlepeer-review

415 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)935-942
Number of pages8
JournalJournal of Clinical Oncology
Issue number5
StatePublished - Dec 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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