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

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.

Application of Physiologically Based Pharmacokinetic Modeling to Characterize the Effects of Age and Obesity on the Disposition of Levetiracetam in the Pediatric Population.

BACKGROUND: Levetiracetam is an antiseizure medication used for several seizure types in adults and children aged 1 month and older; however, due to a lack of data, pharmacokinetic (PK) variability of levetiracetam is not adequately characterized in certain populations, particularly neonates, children younger than 2 years of age, and children older than 2 years of age with obesity. OBJECTIVE: This study aimed to address the gap by leveraging PK data from two prospective standard-of-care pediatric trials (n = 88) covering an age range from 1 month to 19 years, including those with obesity (64%), and applying a physiologically based PK (PBPK) modeling framework. METHODS: A published PBPK model of levetiracetam for children aged 2 years and older was extended to pediatric patients younger than 2 years of age and patients older than 2 years of age with obesity by accounting for the obesity and age-related changes in PK using PK-Sim® software. The prospective pediatric data, along with the literature data for neonates and children younger than 2 years of age, were used to evaluate the extended PBPK models. RESULTS: Overall, 82.4% of data fell within the 90% interval of model-predicted concentrations, with an average fold error within twofold of the accepted criteria. PBPK modeling revealed that children with obesity had lower weight-normalized clearances (0.053 L/h/kg) on average than children without obesity (0.063 L/h/kg). The effect of maturation was well-characterized, resulting in comparable PBPK-simulated, weight-normalized clearances for neonates and children younger than 2 years of age reported from the literature. CONCLUSIONS: PBPK modeling simulations revealed that the current US FDA-labeled pediatric dosing regimen listed in the prescribing information can produce the required exposure of levetiracetam in these target populations with dose adjustments for children with obesity aged 4 years to younger than 16 years.