Open AccessModel‐Informed Drug Development for Everolimus Dosing Selection in Pediatric Infant Patients
Author(s) -
Combes Francois Pierre,
Einolf Heidi J.,
Coello Neva,
Heimbach Tycho,
He Handan,
Grosch Kai
Publication year - 2020
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/psp4.12502
Subject(s) - tuberous sclerosis , everolimus , medicine , dosing , pharmacodynamics , pharmacokinetics , refractory (planetary science) , nonmem , population , pediatrics , drug , pharmacology , physics , environmental health , psychiatry , astrobiology
Everolimus is currently approved in Europe as an adjunctive therapy for patients aged ≥ 2 years with tuberous sclerosis complex (TSC)–associated treatment‐refractory partial‐onset seizures, based on the EXIST‐3 study (NCT01713946) results. As TSC‐associated seizures can also affect children aged between 6 months and 2 years, a modeling and simulation (M&S) approach was undertaken to extrapolate exposure (trough plasma concentration (C min )) after a dose of 6 mg/m 2 and reduction in seizure frequency (RSF). A physiologically based pharmacokinetic model using Simcyp was developed to predict C min in adult and pediatric patients, which was then used by a population pharmacodynamic model and a linear mixed effect model to predict short‐term and long‐term efficacy in adults (for validation) and in children, respectively. Based on the results of the M&S study, everolimus at the dose of 6 mg/m 2 is anticipated to be an efficacious treatment in children 6 months to 2 years of age (up to 77.8% RSF) with concentrations within the recommended target range.