Integrating Dynamic Positron Emission Tomography and Conventional Pharmacokinetic Studies to Delineate Plasma and Tumor Pharmacokinetics of FAU a Prodrug Bioactivated by Thymidylate Synthase

摘要

FAU, a pyrimidine nucleotide analog, is a prodrug bioactivated by intracellular thymidylate synthase to form FMAU that is incorporated into DNA causing cell death. This study presents a model-based approach to integrating dynamic positron emission tomography (PET) and conventional plasma pharmacokinetic studies to characterize the plasma and tissue pharmacokinetics of FAU and FMAU. Twelve cancer patients were enrolled into a phase I study, where conventional plasma pharmacokinetic evaluation of therapeutic FAU (50 – 1600 mg/m²) and dynamic PET assessment of ¹⁸F-FAU were performed. A parent-metabolite population pharmacokinetic model was developed to simultaneously fit PET-derived tissue data and conventional plasma pharmacokinetic data. The developed model enabled separation of PET-derived total tissue concentrations into the parent drug and metabolite components. The model provides quantitative, mechanistic insights into the bioactivation of FAU and retention of FMAU in normal and tumor tissues, and has potential utility to predict tumor responsiveness to FAU treatment.