Sources of pharmacokinetic and pharmacodynamic variability and clinical pharmacology studies of antiseizure medications in the pediatric population

Abstract

Multiple treatment options exist for children with epilepsy, including surgery, dietary therapies, neurostimulation, and antiseizure medications (ASMs). ASMs are the first line of therapy, and more than 30 ASMs have U.S. Food and Drug Administration (FDA) approval for the treatment of various epilepsy and seizure types in children. Given the extensive FDA approval of ASMs in children, it is crucial to consider how the physiological and developmental changes throughout childhood may impact drug disposition. Various sources of pharmacokinetic (PK) variability from different extrinsic and intrinsic factors such as patients' size, age, drug-drug interactions, and drug formulation could result in suboptimal dosing of ASMs. Barriers exist to conducting clinical pharmacological studies in neonates, infants, and children due to ethical and practical reasons, limiting available data to fully characterize these drugs' disposition and better elucidate sources of PK variability. Modeling and simulation offer ways to circumvent traditional and intensive clinical pharmacology methods to address gaps in epilepsy and seizure management in children. This review discusses various physiological and developmental changes that influence the PK and pharmacodynamic (PD) variability of ASMs in children, and several key ASMs will be discussed in detail. We will also review novel trial designs in younger pediatric populations, highlight the role of extrapolation of efficacy in epilepsy, and the use of physiologically based PK modeling as a tool to investigate sources of PK/PD variability in children. Finally, we will conclude with current challenges and future directions for optimizing the efficacy and safety of these drugs across the pediatric age spectrum.