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

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 (Cmin) 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. Cmin 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 (