van Dijkman SC, et al. – This research was meant to evaluate pharmacokinetic (PK) drug–drug interactions (DDIs) and dosing rationale for antiepileptic drugs (AEDs) in adults and children. The authors suggested that the available clinical guidelines must take into account for the effects of DDI on AED exposure. Moreover, appropriate dosing recommendations must be followed for adult and paediatric patients who require combination therapy.

Methods

• For this research, models describing the pharmacokinetics of carbamazepine, clobazam, clonazepam, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, valproic acid, and zonisamide in adult and paediatric patients were accumulated from the published literature and implemented in NONMEM v7.2.
• Taking current clinical practice into account, the explore simulation scenarios to characterise AED exposure in virtual patients receiving mono–, and polytherapy. 
• For the purpose of this analysis, Css, Cmax and Cmin were selected as parameters.

Results

• Their investigations displayed that DDIs could cause major changes in AED concentrations both in adults and children.
• They described that when more than one AED was used, even larger changes were observed in the concentrations of the primary drug, leading to significant differences in Css between mono– and polytherapy for most AEDs.
• These findings indicated that currently recommended dosing algorithms and titration procedures did not ensure attainment of appropriate therapeutic concentrations.