Translational Pharmacokinetic-Pharmacodynamic Modeling and Simulation: Optimizing 5-Fluorouracil Dosing in Children With Pediatric Ependymoma.
We previously investigated novel therapies for pediatric ependymoma and found 5-fluorouracil (5-FU) i.v. bolus increased survival in a representative mouse model. However, without a quantitative framework to derive clinical dosing recommendations, we devised a translational pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation approach. Results from our preclinical PK-PD model suggested tumor concentrations exceeded the 1-hour target exposure (in vitroIC90), leading to tumor growth delay and increased survival. Using an adult population PK model, we scaled our preclinical PK-PD model to children. To select a 5-FU dosage for our clinical trial in children with ependymoma, we simulated various 5-FU dosages for tumor exposures and tumor growth inhibition, as well as considering tolerability to bolus 5-FU administration. We developed a pediatric population PK model of bolus 5-FU and simulated tumor exposures for our patients. Simulations for tumor concentrations indicated that all patients would be above the 1-hour target exposure for antitumor effect.
Department of Pharmaceutical Sciences St. Jude Children's Research Hospital Memphis Tennessee USA.
V M
VM
Daryani
Department of Pharmaceutical Sciences St. Jude Children's Research Hospital Memphis Tennessee USA.
Y T
YT
Patel
Genentech South San Francisco California USA.
M
M
Tagen
Quantitative Pharmacology and Pharmacometrics Merck Research Laboratories Rahway New Jersey USA.
D C
DC
Turner
Preclinical Therapeutics and Drug Delivery Research Program Hospital Sant Joan de Déu Barcelona Barcelona Spain.
A M
AM
Carcaboso
Department of Pediatrics Pennsylvania State College of Medicine Hershey Pennsylvania USA.
J M
JM
Atkinson
Department of Oncology St. Jude Children's Research Hospital Memphis Tennessee USA.
A
A
Gajjar
Cambridge Cancer Centre Cambridge UK.
R J
RJ
Gilbertson
Department of Oncology St. Jude Children's Research Hospital Memphis Tennessee USA.
K D
KD
Wright
Department of Pharmaceutical Sciences St. Jude Children's Research Hospital Memphis Tennessee USA.
C F
CF
Stewart
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D001798:Blood Proteins / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D054796:Drug Dosage Calculations; D004806:Ependymoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011485:Protein Binding; D011897:Random Allocation
D000964:Antimetabolites, Antineoplastic; D001798:Blood Proteins; D005472:Fluorouracil