Integrating Dynamic Positron Emission Tomography and Conventional Pharmacokinetic Studies to Delineate Plasma and Tumor Pharmacokinetics of FAU, a Prodrug Bioactivated by Thymidylate Synthase.
FAU, a pyrimidine nucleotide analogue, is a prodrug bioactivated by intracellular thymidylate synthase to form FMAU, which 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 1 study, where conventional plasma pharmacokinetic evaluation of therapeutic FAU (50-1600 mg/m2 ) and dynamic PET assessment of 18 F-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.
['Li|Jing|J|', 'Kim|Seongho|S|', 'Shields|Anthony F|AF|', 'Douglas|Kirk A|KA|', 'McHugh|Christopher I|CI|', 'Lawhorn-Crews|Jawana M|JM|', 'Wu|Jianmei|J|', 'Mangner|Thomas J|TJ|', 'LoRusso|Patricia M|PM|']
D001086:Arabinofuranosyluracil D006801:Humans D007262:Infusions, Intravenous D009369:Neoplasms D049268:Positron-Emission Tomography D011355:Prodrugs D013940:Thymidylate Synthase
tumor pharmacokinetics thymidylate synthase positron emission tomography (PET) parent-metabolite population pharmacokinetic model 1-(2′-deoxy-2′-fluoro-β-d-arabinofuranosyl) uracil (FAU)