Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients.
OBJECTIVE
To evaluate the basic pharmacokinetic (PK) characteristics of imatinib mesylate and assess the relationship between the PK and pharmacodynamic (PD) properties of the drug.


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 microg/mL (approximately 1 micromol/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.


CONCLUSIONS
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.
Clinical Pharmacology, Novartis, One Health Plaza, Building 419, Room 2368, East Hanover, NJ 07936-1080, USA. bin.peng@pharma.novartis.com
Bin
B
Peng
Michael
M
Hayes
Debra
D
Resta
Amy
A
Racine-Poon
Brian J
BJ
Druker
Moshe
M
Talpaz
Charles L
CL
Sawyers
Marianne
M
Rosamilia
John
J
Ford
Peter
P
Lloyd
Renaud
R
Capdeville
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001549:Benzamides; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012720:Severity of Illness Index; D016019:Survival Analysis; D016896:Treatment Outcome
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate