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 (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.