Whole-body physiology-based pharmacokinetic modeling of Osimertinib in PET/CT and therapeutic doses

Abstract

Introduction: Osimertinib, a tyrosine kinase inhibitor (TKI), is indicated to treat patients with EGFR (epidermal growth factor receptor) mutated non-small cell lung cancer (NSCL). TKIs have a narrow therapeutic range, risking toxicity or nonresponse. Spatial tumor heterogeneity results in sanctuary sites with some neoplastic cells receiving insufficient TKI concentrations during the treatment. Personalized dosing may refine the current "one dose fits all" paradigm that currently dominates the field. Imaging by positron emission tomography (PET) with micro-dosed inertly radioactively labeled drugs can be used to identify these sanctuary sites and quantify drug uptake at the site of action in oncological patients. Methods: A whole-body physiology-based pharmacokinetic (PBPK ) model was developed based on the previous publication. Physicochemical properties, drug-specific characteristics and key NSCLC hallmarks (immune tumor deprivation, unaltered tumor perfusion, acidic tumor environment) were considered. Predicting therapeutic pharmacokinetic ( PK) involved incorporating saturable EGFR binding, target affinity and abundance. Evaluation included observed therapeutic PK in blood after oral dosing in ten healthy volunteers. Time activity curves from blood samples and PET images of dynamic scans quantified after intravenous ( IV) micro-dosing in four NSCLC patients. The model accuracy was determined by comparing predicted and observed plasma and tissue concentrations with a two-fold prediction error (PE) tolerance.