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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‐pharmacod...

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Detalles Bibliográficos
Autores principales: Daryani, VM, Patel, YT, Tagen, M, Turner, DC, Carcaboso, AM, Atkinson, JM, Gajjar, A, Gilbertson, RJ, Wright, KD, Stewart, CF
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834132/
https://www.ncbi.nlm.nih.gov/pubmed/27104090
http://dx.doi.org/10.1002/psp4.12075
Descripción
Sumario: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.