Data Analyst The Life Raft Group Star Tannery, Virginia, United States
Objective: Therapeutic drug monitoring (TDM) of imatinib in gastrointestinal stromal tumor (GIST) patients is typically based on total plasma levels, despite imatinib being >95% protein-bound. Only the unbound fraction enters target cells and drives efficacy. Binding to alpha-1-acid glycoprotein (AGP) can inflate total imatinib measurements and represents a potential pitfall in interpreting plasma levels, potentially misrepresenting effective exposure.
Methods: We adapted a published pharmacokinetic model to create a user-friendly calculator implemented as an Excel spreadsheet, which estimates the effective imatinib concentration adjusted for protein binding (Cadjusted) by using measured total imatinib (Ctot) and AGP levels. The calculator first estimates the unbound imatinib concentration (Cu), representing the concentration of pharmacologically active, free drug, before calculating the adjusted total concentration (Cadjusted). The model assumes non-linear, 1:1 binding with AGP (dissociation constant Kd = 319 ng/mL) and applies a correction formula derived from Haouala et al., 2012 (Br J Clin Pharmacol). Cadjusted represents the total concentration normalized to a standard AGP level, improving interpretability of pharmacologically active drug exposure.
Results: Sample scenarios illustrate how AGP levels affect effective drug exposure. For example, at Ctot = 1200 ng/mL and AGP = 1.5 g/L, Cadjusted is 808 ng/mL; with AGP = 0.9 g/L, Cadjusted increases to 1329 ng/mL. These shifts highlight the importance of accounting for protein binding when interpreting TDM results.
Conclusion: This calculator provides a practical tool for estimating protein-binding–adjusted imatinib exposure. By aiding in the understanding of AGP-related binding as a potential pitfall, it may help refine therapeutic drug monitoring and support more precise dosing in GIST patients.
Sample Outputs from Protein-Binding–Adjusted Imatinib Calculator
