Open AccessTranslational Pharmacokinetic‐Pharmacodynamic Modeling and Simulation: Optimizing 5‐Fluorouracil Dosing in Children With Pediatric Ependymoma
Author(s) -
Daryani VM,
Patel YT,
Tagen M,
Turner DC,
Carcaboso AM,
Atkinson JM,
Gajjar A,
Gilbertson RJ,
Wright KD,
Stewart CF
Publication year - 2016
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12075
Subject(s) - ependymoma , medicine , tolerability , dosing , pharmacokinetics , pharmacodynamics , bolus (digestion) , fluorouracil , pharmacology , population , oncology , chemotherapy , adverse effect , surgery , environmental health
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 vitro IC 90 ), 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.