Population pharmacokinetics and pharmacogenetics of imatinib in children and adults.

Abstract

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 alpha1-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.

• Authors: Aurélie Petain, Darouna Kattygnarath, Julie Azard, Etienne Chatelut, Catherine Delbaldo, Birgit Geoerger, Michel Barrois, Sophie Séronie-Vivien, Axel LeCesne, Gilles Vassal, Innovative Therapies with Children with Cancer European consortium
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 21 Pg. 7102-9 (Nov 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18981009 (Publication Type: Journal Article)

Chemical References

• Benzamides
• Blood Proteins
• CGP 74588
• Glycoproteins
• Piperazines
• Pyrimidines
• Serum Albumin
• Imatinib Mesylate

Topics

• Adolescent
• Adult
• Age Factors
• Aged
• Aged, 80 and over
• Benzamides
• Blood Proteins (metabolism)
• Body Weight
• Child
• Child, Preschool
• Gastrointestinal Stromal Tumors (genetics, metabolism)
• Glycoproteins (blood)
• Humans
• Imatinib Mesylate
• Metabolic Clearance Rate (genetics)
• Middle Aged
• Pharmacogenetics
• Piperazines (metabolism, pharmacokinetics, pharmacology)
• Polymorphism, Genetic
• Population Groups
• Pyrimidines (metabolism, pharmacokinetics, pharmacology)
• Serum Albumin
• Sex Factors
• Young Adult