Clinical pharmacokinetics of imatinib and its therapeutic relevance

Details

Serval ID
serval:BIB_4D7D4CB0B535
Type
A part of a book
Publication sub-type
Chapter: chapter ou part
Collection
Publications
Institution
Title
Clinical pharmacokinetics of imatinib and its therapeutic relevance
Title of the book
Imatinib: Chemical structure, pharmacology and adverse effects
Author(s)
Widmer N., Gotta V., Haouala A., Blanc J., von Mehren M., Duchosal M., Leyvraz S., Csajka C., Decosterd L.A., Buclin T.
Publisher
Nova Science Publishers
Address of publication
New York
ISBN
978-1-62808-297-5
Publication state
Published
Issued date
2013
Editor
Akhtari M., Elhemaidi I.
Chapter
2
Pages
15-43
Language
english
Abstract
The pharmacokinetic profile of imatinib has been assessed in healthy subjects and in population studies among thousands of patients with CML or GIST. Imatinib is rapidly and extensively absorbed from the GI tract, reaching a peak plasma concentration (Cmax) within 1-4 h following administration. Imatinib bioavailability is high (98%) and independent of food intake. Imatinib undergoes rapid and extensive distribution into tissues, with minimal penetration into the central nervous system. In the circulation, it is approximately 95% bound to plasma proteins, principally α1-acid glycoprotein (AGP) and albumin. Imatinib undergoes metabolism in the liver via the cytochrome P450 enzyme system (CYP), with CYP3A4 being the main isoenzyme involved. The N-desmethyl metabolite CGP74588 is the major circulating active metabolite. The typical elimination half-life for imatinib is approximately 14-22 h. Imatinib is characterized by large inter-individual pharmacokinetic variability, which reflects in a wide spread of concentrations observed under standard dosage. Besides adherence, several factors have been shown to influence this variability, especially demographic characteristics (sex, age, body weight and disease diagnosis), blood count characteristics, enzyme activity (mainly CYP3A4), drug interactions, activity of efflux transporters and plasma levels of AGP.
Additionally, recent retrospective studies have shown that drug exposure, reflected in either the area under the concentration-time curve (AUC) or more conveniently the trough level (Cmin), correlates with treatment outcomes. Increased toxicity has been associated with high plasma levels, and impaired clinical efficacy with low plasma levels. While no upper concentration limit has been formally established, a lower limit for imatinib Cmin of about 1000 ng/mL has been proposed repeatedly for improving outcomes in CML and GIST patients.
Imatinib is licensed for use in chronic phase CML and GIST at a fixed dose of 400 mg once daily (600 mg in some other indications) despite substantial pharmacokinetic variability caused by both genetic and acquired factors. The dose can be modified on an individual basis in cases of insufficient response or substantial toxic effects. Imatinib would, however, meet traditional criteria for a therapeutic drug monitoring (TDM) program: long-term therapy, measurability, high inter-individual but restricted intra-individual variability, limited pharmacokinetic predictability, effect of drug interactions, consistent association between concentration and response, suggested therapeutic threshold, reversibility of effect and absence of early markers of efficacy and toxic effects. Large-scale, evidence-based assessments of drug concentration monitoring are therefore still warranted for the personalization of imatinib treatment.
Create date
23/09/2013 10:23
Last modification date
20/08/2019 14:02
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