Population Pharmacokinetics and Pharmacogenetics of Imatinib in Children and Adults

Purpose: The aim of this study was to explore the effect of several demographic, biological, and pharmacogenetic covariates on the disposition of imatinib and its main metabolite (CGP74588) in both adults and children. Experimental Design: Thirty-three children with solid malignancies included in a...

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Published in:	Clinical cancer research Vol. 14; no. 21; pp. 7102 - 7109
Main Authors:	RETAIN, Aurélie, KATTYGNARATH, Darouna, AZARD, Julie, CHATELUT, Etienne, DELBALDO, Catherine, GEOERGER, Birgit, BARROIS, Michel, SERONIE-VIVIEN, Sophie, LECESNE, Axel, VASSAL, Gilles
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-11-2008
Subjects:	ABCG2 Adolescent Adult Age Factors Aged Aged, 80 and over Antineoplastic agents Benzamides Biological and medical sciences Blood Proteins - metabolism Body Weight Child Child, Preschool Gastrointestinal Stromal Tumors - genetics Gastrointestinal Stromal Tumors - metabolism Glycoproteins - blood Humans imatinib Imatinib Mesylate Medical sciences Metabolic Clearance Rate - genetics Middle Aged pediatrics Pharmacogenetics Pharmacology. Drug treatments Piperazines - metabolism Piperazines - pharmacokinetics Piperazines - pharmacology Polymorphism, Genetic Population Groups population pharmacokinetics Pyrimidines - metabolism Pyrimidines - pharmacokinetics Pyrimidines - pharmacology Serum Albumin Sex Factors Young Adult Human Antineoplastic agent Population pharmacokinetics Imatinib Pharmacogenetics Enzyme Tyrosine kinase inhibitor Transferases Enzyme inhibitor Genetics Adult Child Protein-tyrosine kinase
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Summary:	Purpose: The aim of this study was to explore the effect of several demographic, biological, and pharmacogenetic covariates on the disposition of imatinib and its main metabolite (CGP74588) in both adults and children. Experimental Design: Thirty-three children with solid malignancies included in a phase II exploratory study and 34 adults with gastrointestinal stromal tumors received 340 mg/m 2 and 400 mg imatinib, respectively. Plasma imatinib and CGP74588 concentrations observed on day 1 and at steady-state were analyzed by a population pharmacokinetic method (NONMEM) to evaluate the effect of age, body weight, age, sex, albuminemia, plasma α1-acid glycoprotein (AGP), and eight polymorphisms corresponding to ABCB1, ABCG2, CYP3A4, CYP3A5 , and AGP (pharmacogenetic data available for 46 of 67 patients). Results: Analysis of the whole data set in 67 patients showed that apparent clearance (CL/F) of imatinib was positively correlated with body weight and albuminemia and negatively with AGP. By considering these three covariates, the interindividual variability on CL/F decreased from 47% to 19%. The apparent clearance of CGP74588 was similarly dependent on both body weight and AGP and significantly lower (30% reduction) at steady-state. By adding genotype status to the final covariate imatinib model, a 22% reduction in CL/F was observed in heterozygous compared with wild-type patients corresponding to ABCG2 c.421C>A ( P < 0.05). Conclusions: By considering morphologic and biological covariates, a unique covariate model could be used to accurately describe imatinib pharmacokinetics in patients ages 2 to 84 years. Morphologic and biological characteristics have a stronger influence than pharmacogenetics on imatinib pharmacokinetics.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1078-0432 1557-3265
DOI:	10.1158/1078-0432.CCR-08-0950