Precision Medicine in Oncology: Imatinib Dosing in the Obese Cancer Population Using Virtual Clinical Trials.

Publisher: Wiley Country of Publication: United States NLM ID: 101580011 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2163-8306 (Electronic) Linking ISSN: 21638306 NLM ISO Abbreviation: CPT Pharmacometrics Syst Pharmacol Subsets: MEDLINE

Publication: 2015- : Hoboken, NJ : Wiley
Original Publication: New York, NY : Nature Pub. Group

Imatinib Mesylate*/pharmacokinetics ; Imatinib Mesylate*/administration & dosage ; Obesity*/complications ; Obesity*/metabolism ; Precision Medicine*/methods ; Neoplasms*/drug therapy ; Neoplasms*/complications ; Neoplasms*/metabolism ; Antineoplastic Agents*/pharmacokinetics ; Antineoplastic Agents*/administration & dosage; Humans ; Male ; Middle Aged ; Female ; Body Mass Index ; Drug Monitoring/methods ; Models, Biological ; Aged ; Adult ; Computer Simulation ; Dose-Response Relationship, Drug ; Cytochrome P-450 CYP3A/metabolism ; Clinical Trials as Topic ; Body Surface Area

This study investigates the impact of obesity on imatinib pharmacokinetics in cancer patients by utilizing physiologically based pharmacokinetic modeling (PBPK) and virtual clinical trial approaches and evaluates the effectiveness of therapeutic drug monitoring (TDM)-guided dose adjustment to recover the imatinib trough concentration (C min ) into the target concentration. PBPK models were validated against clinical data from lean, overweight, and obese cancer populations. Simulations revealed significant physiological differences across body-mass-index categories, including higher body surface area, liver weight, and cardiac output in obese individuals, coupled with lower CYP3A4 enzyme activity and hematocrit levels, which translated into pharmacokinetic differences. Obese patients exhibited significantly lower imatinib maximum concentration and area-under-the-curve values. C min levels, a key determinant of therapeutic response, were consistently lower in the obese cohort, with a greater proportion of individuals falling below the subtherapeutic threshold (< 750 ng/mL); nevertheless, the differences are not statistically significant. TDM-guided dose adjustments improved C min levels across BMI groups. For patients with C min between 450 and 750 ng/mL, dose increases of 1.5-2.0 times effectively restored levels to the target range (750-1500 ng/mL). However, individuals with C min < 450 ng/mL often failed to achieve therapeutic levels, suggesting limited benefit from further dose escalation and a need for alternative therapies. This study underscores the importance of PBPK modeling and TDM in tailoring imatinib therapy for obese cancer patients by addressing physiological differences and optimizing dosing strategies for better outcomes.
(© 2025 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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Keywords: PBPK; TDM; cancer obesity; imatinib; pharmacokinetics

8A1O1M485B (Imatinib Mesylate)
0 (Antineoplastic Agents)
EC 1.14.14.1 (Cytochrome P-450 CYP3A)

Date Created: 20250328 Date Completed: 20250616 Latest Revision: 20250618

20250618

PMC12167919

10.1002/psp4.70018

40150877