Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients
| Autor: | Moshe Talpaz, Renaud Capdeville, Peter Lloyd, Charles L. Sawyers, Amy Racine-Poon, Michael Hayes, Debra Resta, Brian J. Druker, Bin Peng, Marianne Rosamilia, John Ford |
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| Rok vydání: | 2004 |
| Předmět: |
Adult
Male Cancer Research Maximum Tolerated Dose Administration Oral Biological Availability Pharmacology Severity of Illness Index Drug Administration Schedule Piperazines Pharmacokinetics Oral administration hemic and lymphatic diseases Leukemia Myelogenous Chronic BCR-ABL Positive Medicine Humans Dosing Aged Dose-Response Relationship Drug business.industry Imatinib Middle Aged medicine.disease Survival Analysis Leukemia Dose–response relationship Imatinib mesylate Pyrimidines Treatment Outcome Oncology Pharmacodynamics Benzamides Imatinib Mesylate Female business medicine.drug Follow-Up Studies |
| Zdroj: | Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 22(5) |
| ISSN: | 0732-183X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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