Population pharmacokinetics of imatinib mesylate and its metabolite in children and young adults.
BACKGROUND
Imatinib mesylate (Gleevec) is a small molecule tyrosine kinase inhibitor approved for use in the management of chronic myeloid leukemia in adults and children and in gastrointestinal stromal tumors in adults. Population pharmacokinetic (PPK) studies evaluating the effect of population covariates on the pharmacokinetics of imatinib and its active metabolite have been developed in adults with chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). However, this still remains to be described in children.


OBJECTIVE
The objectives of the analysis were to develop a PPK model of imatinib and its active metabolite, CGP74588, to describe exposure in children and young adults and to identify covariates that are predictors of variability in disposition.


METHODS
Plasma concentrations from 26 subjects with Philadelphia (Ph+) leukemia (Phase I study) and 15 subjects with refractory solid tumors (Phase II study), who received oral imatinib at doses ranging from 260 to 570 mg/m(2), were available for the PPK analysis in NONMEM. Blood samples were drawn prior to dosing and over 24-48 h on days 1 and 8 of the studies. Covariates studied included weight, age, albumin, alanine aminotransferase and the study population.


RESULTS
The pharmacokinetics of imatinib and CGP 74588 were well described by one and two compartment models, respectively. Total body weight was the only covariate found to significantly affect Cl/F and V/F. The final imatinib-CGP 74588 model is summarized as follows: CL/F (imatinib) (L/h) = 10.8 x (WT/70)(0.75), V/F (imatinib) (L) = 284 x (WT/70) and D1(duration of zero order absorption,imatinib) (h) = 1.67 and CL/F (CGP 74588) (L/h) = 9.65 x (WT/70)(0.75), V1/F (CGP 74588) (L) = 11.6 x (WT/70), Q (CGP 74588) (L/h) = 2.9 x (WT/70)(0.75) and V2/F (CGP 74588) (L) = 256*(WT/70). Model evaluation indicated that the final model was robust and satisfactory.


CONCLUSIONS
Current imatinib dosing guidelines in pediatrics is based on the achievement of exposures consistent with doses known to be safe and efficacious in adults. Dose adjustments in children are guided empirically by the observance of drug-related toxicities. While, the pharmacokinetics of imatinib and its active metabolite, CGP 74588 in children are consistent with prior knowledge in adults, the model will form the basis to support the design of future trials, particularly with a view to managing toxicities and exploring dosing in this population.
Menon-Andersen
Divya
D
The Children's Hospital of Philadelphia, 34th and Civic Center Blvd, Philadelphia, PA 19104, USA. menond@email.chop.edu
Mondick
John T
JT
Jayaraman
Bhuvana
B
Thompson
Patrick A
PA
Blaney
Susan M
SM
Bernstein
Mark
M
Bond
Mason
M
Champagne
Martin
M
Fossler
Michael J
MJ
Barrett
Jeffrey S
JS
D000284:Administration, Oral; D000293:Adolescent; D000375:Aging / Q000097:blood / Q000378:metabolism; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001549:Benzamides; D002648:Child; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D015999:Multivariate Analysis; D010879:Piperazines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011743:Pyrimidines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult
D000970:Antineoplastic Agents; D001549:Benzamides; C464561:CGP 74588; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate