TY - JOUR
T1 - Pharmacotherapy in pediatric epilepsy
T2 - from trial and error to rational drug and dose selection – a long way to go
AU - van Dijkman, Sven C.
AU - Alvarez-Jimenez, Ricardo
AU - Danhof, Meindert
AU - Della Pasqua, Oscar
PY - 2016/10/2
Y1 - 2016/10/2
N2 - Introduction: Whereas ongoing efforts in epilepsy research focus on the underlying disease processes, the lack of a physiologically based rationale for drug and dose selection contributes to inadequate treatment response in children. In fact, limited information on the interindividual variation in pharmacokinetics and pharmacodynamics of anti-epileptic drugs (AEDs) in children drive prescription practice, which relies primarily on dose regimens according to a mg/kg basis. Such practice has evolved despite advancements in pediatric pharmacology showing that growth and maturation processes do not correlate linearly with changes in body size. Areas covered: In this review we aim to provide 1) a comprehensive overview of the sources of variability in the response to AEDs, 2) insight into novel methodologies to characterise such variation and 3) recommendations for treatment personalisation. Expert opinion: The use of pharmacokinetic-pharmacodynamic principles in clinical practice is hindered by the lack of biomarkers and by practical constraints in the evaluation of polytherapy. The identification of biomarkers and their validation as tools for drug development and therapeutics will require some time. Meanwhile, one should not miss the opportunity to integrate the available pharmacokinetic data with modeling and simulation concepts to prevent further delays in the development of personalised treatments for pediatric patients.
AB - Introduction: Whereas ongoing efforts in epilepsy research focus on the underlying disease processes, the lack of a physiologically based rationale for drug and dose selection contributes to inadequate treatment response in children. In fact, limited information on the interindividual variation in pharmacokinetics and pharmacodynamics of anti-epileptic drugs (AEDs) in children drive prescription practice, which relies primarily on dose regimens according to a mg/kg basis. Such practice has evolved despite advancements in pediatric pharmacology showing that growth and maturation processes do not correlate linearly with changes in body size. Areas covered: In this review we aim to provide 1) a comprehensive overview of the sources of variability in the response to AEDs, 2) insight into novel methodologies to characterise such variation and 3) recommendations for treatment personalisation. Expert opinion: The use of pharmacokinetic-pharmacodynamic principles in clinical practice is hindered by the lack of biomarkers and by practical constraints in the evaluation of polytherapy. The identification of biomarkers and their validation as tools for drug development and therapeutics will require some time. Meanwhile, one should not miss the opportunity to integrate the available pharmacokinetic data with modeling and simulation concepts to prevent further delays in the development of personalised treatments for pediatric patients.
KW - Antiepileptic drugs
KW - dose rationale
KW - epilepsy
KW - epileptic seizures
KW - modelling and simulation
KW - paediatrics
KW - personalised medicine
KW - pharmacokinetic-pharmacodynamic relationships
KW - pharmacokinetics
KW - translational pharmacology
UR - http://www.scopus.com/inward/record.url?scp=84987784723&partnerID=8YFLogxK
U2 - https://doi.org/10.1080/17425255.2016.1203900
DO - https://doi.org/10.1080/17425255.2016.1203900
M3 - Review article
C2 - 27434782
SN - 1742-5255
VL - 12
SP - 1143
EP - 1156
JO - Expert Opinion on Drug Metabolism and Toxicology
JF - Expert Opinion on Drug Metabolism and Toxicology
IS - 10
ER -