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 Druker, Moshe Talpaz, Charles L. Sawyers, Marianne Rosamilia, John Ford, Peter Lloyd, Renaud Capdeville

Research output: Contribution to journalArticle

376 Citations (Scopus)

Abstract

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
Volume22
Issue number5
DOIs
StatePublished - 2004
Externally publishedYes

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Pharmacokinetics
Pharmaceutical Preparations
Philadelphia Chromosome
Imatinib Mesylate
Inhibitory Concentration 50
Oral Administration
Leukemia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. / Peng, Bin; Hayes, Michael; Resta, Debra; Racine-Poon, Amy; Druker, Brian; Talpaz, Moshe; Sawyers, Charles L.; Rosamilia, Marianne; Ford, John; Lloyd, Peter; Capdeville, Renaud.

In: Journal of Clinical Oncology, Vol. 22, No. 5, 2004, p. 935-942.

Research output: Contribution to journalArticle

Peng, B, Hayes, M, Resta, D, Racine-Poon, A, Druker, B, Talpaz, M, Sawyers, CL, Rosamilia, M, Ford, J, Lloyd, P & Capdeville, R 2004, 'Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients', Journal of Clinical Oncology, vol. 22, no. 5, pp. 935-942. https://doi.org/10.1200/JCO.2004.03.050
Peng, Bin ; Hayes, Michael ; Resta, Debra ; Racine-Poon, Amy ; Druker, Brian ; Talpaz, Moshe ; Sawyers, Charles L. ; Rosamilia, Marianne ; Ford, John ; Lloyd, Peter ; Capdeville, Renaud. / Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. In: Journal of Clinical Oncology. 2004 ; Vol. 22, No. 5. pp. 935-942.
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abstract = "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.",
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T1 - Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients

AU - Peng, Bin

AU - Hayes, Michael

AU - Resta, Debra

AU - Racine-Poon, Amy

AU - Druker, Brian

AU - Talpaz, Moshe

AU - Sawyers, Charles L.

AU - Rosamilia, Marianne

AU - Ford, John

AU - Lloyd, Peter

AU - Capdeville, Renaud

PY - 2004

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N2 - 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.

AB - 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.

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