Pharmacokinetic Considerations in the Treatment of Childhood Epilepsy

Tolerability and efficacy of perampanel in children with refractory epilepsy

“…Repeated therapeutic trials with antiepileptic drugs (AEDs) are common in paediatric medically refractory epilepsy, especially in children with Lennox–Gastaut syndrome, severe myoclonic epilepsy of infancy, cerebral palsy, brain injuries and malformations, and hereditary metabolic or degenerative disorders . Data regarding the effectiveness of new AEDs are initially provided by epilepsy trials in adults, although differences in AED pharmacokinetics, epilepsy etiology, and presence of comorbidities can affect both their efficacy and tolerability in children …”

“…1 Data regarding the effectiveness of new AEDs are initially provided by epilepsy trials in adults, although differences in AED pharmacokinetics, epilepsy etiology, and presence of comorbidities can affect both their efficacy and tolerability in children. [2][3][4] Perampanel is a selective, noncompetitive antagonist of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors on postsynaptic neurons, and is the first drug of the new AED class of AMPA-type glutamate receptor antagonists. 5 The elimination half-life of perampanel is 105 hours and allows for once-daily dosing.…”

The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments

“…The age‐dependent changes in pharmacodynamics are often not readily distinguished from pharmacogenetic and pharmacokinetic considerations, but it is broadly accepted that the actions of drugs may alter with developmental stages (204). From a pharmacokinetic perspective, the drug absorption, distribution, metabolism, and excretion processes all show age‐dependent changes (206). A higher plasma clearance of hepatically metabolised drugs has been consistently observed in children under 10 years of age compared with adults, which may necessitate the use of higher weight‐adjusted dosages in children (204, 205).…”

“…In children, steady‐state blood levels of lithium can therefore be obtained after approximately four days, and higher dosages may be required because of this, and also because of the greater volume of distribution and lower brain‐to‐serum‐lithium ratios (205, 208). The need for higher dosages per unit of body weight in children relative to adults may be mistaken for treatment nonadherence, and vice versa (206). In order to minimise ADRs, the use of low starting dosages and gradual dose titration are recommended for children and adolescents (209).…”

“…Safety data for psychotropic medications in children and adolescents are limited (210), but preschool‐aged children are at higher risk of ADRs than older children and adolescents (211). A similar range of ADRs is seen in children and adolescents compared with their adult counterparts for lithium, lamotrigine, carbamazepine (208), valproate (212), and atypical antipsychotics (213), but particular considerations in this group relate to cognitive adverse effects and sedation that may affect school performance (206), disturbance of bone growth due to anticonvulsants or hyperprolactinaemia (213), the long‐term sequelae of PCOS and the metabolic syndrome in the young, and the unknown potential effects of these medications on physical growth and brain development (210, 214). For lithium, new‐onset enuresis has been reported as an ADR unique to children in a randomised, placebo‐controlled trial of 91 patients between the ages of five and 13, which together with fatigue, ataxia, vomiting, headache, and stomachache were common ADRs (215).…”