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 of18F-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.
Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA. lijin@karmanos.org.
Jing
J
Li
Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
Seongho
S
Kim
Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
Anthony F
AF
Shields
Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
Kirk A
KA
Douglas
Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
Christopher I
CI
McHugh
Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
Jawana M
JM
Lawhorn-Crews
Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
Jianmei
J
Wu
Department of Radiology, Wayne State University, Detroit, MI, USA.
Thomas J
TJ
Mangner
Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
Patricia M
PM
LoRusso
D001086:Arabinofuranosyluracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D009369:Neoplasms / Q000097:blood* / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography / Q000379:methods*; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D013940:Thymidylate Synthase / Q000378:metabolism*
C457880:2'-fluorodeoxyuracil-arabinofuranoside; D011355:Prodrugs; D001086:Arabinofuranosyluracil; D013940:Thymidylate Synthase
1-(2′-deoxy-2′-fluoro-β-d-arabinofuranosyl) uracil (FAU); parent-metabolite population pharmacokinetic model; positron emission tomography (PET); thymidylate synthase; tumor pharmacokinetics