According to GlaxoSmithKline's Clinical Trial Register, data from the GlaxoSmithKline studies LAM100034 and LEP103944, corresponding to ClinicalTrials.gov identifiers NCT00113165 and NCT00264615, used in this work, have been used in previous publications (doi: https://doi.org/10.1212/01.wnl.0000277698.33743.8b , https://doi.org/10.1111/j.1528-1167.2007.01274.x ).

AIMSPopulation pharmacokinetic modelling has been widely used across many therapeutic areas to identify sources of variability, which are incorporated into models as covariate factors. Despite numerous publications on pharmacokinetic drug-drug interactions (DDIs) between antiepileptic drugs (AEDs), such data are not used to support the dose rationale for polytherapy in the treatment of epileptic seizures. Here we assess the impact of DDIs on plasma concentrations and evaluate the need for AED dose adjustment. METHODSModels describing the pharmacokinetics of carbamazepine, clobazam, clonazepam, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, valproic acid and zonisamide in adult and paediatric patients were collected from the published literature and implemented in NONMEM v7.2. Taking current clinical practice into account, we explore simulation scenarios to characterize AED exposure in virtual patients receiving mono-and polytherapy. Steady-state, maximum and minimum concentrations were selected as parameters of interest for this analysis. RESULTSOur simulations show that DDIs can cause major changes in AED concentrations both in adults and children. When more than one AED is used, even larger changes are observed in the concentrations of the primary drug, leading to significant differences in steady-state concentration between mono-and polytherapy for most AEDs. These results suggest that currently recommended dosing algorithms and titration procedures do not ensure attainment of appropriate therapeutic concentrations. CONCLUSIONSThe effect of DDIs on AED exposure cannot be overlooked. Clinical guidelines must consider such covariate effects and ensure appropriate dosing recommendations for adult and paediatric patients who require combination therapy. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• First-line and alternative first line antiepileptic drugs (AEDs) are often used in combination with second-line line drugs (i.e. add-on).• Many AED combinations lead to pharmacokinetic drug-drug interactions (DDIs), which may result in large variation in drug exposure.• The implications of such DDIs have not been considered in existing clinical guidelines. WHAT THIS STUDY ADDS• We evaluate how demographic and clinical factors, including comedications (polytherapy), affect systemic exposure to AEDs in the target patient population. In addition, we demonstrate that AED dosing regimens can be optimized to ensure drug concentrations are maintained within a reference therapeutic range.• DDIs can lead to significant changes in systemic exposure and potentially alter the efficacy and safety profile of AEDs in adult and paediatric patients.• These results form the basis for a comprehensive review of clinical guidelines for the use of first and second line AEDs, including novel algorithms for dose adjustment.

Abstract, Conclusion section, lines 4-8 which previously readThe availability of an integrated model including the whole patient population provides insight into the role of age-related changes in the disposition of lamotrigine, and potential implications for dose optimisation.should read The availability of an integrated model including the whole patient population provides insight into the role of age-related changes in the disposition of lamotrigine, and potential implications for maintenance dose optimisation in any future trials. Table 4, heading which previously read Optimised dosing regimens and predicted Css per age group should read Optimised maintenance dosing regimens and predicted steady-state concentration (Css) per age group in the simulated scenarios Table 4, footnote which previously read Each column summarises the proportion of patients in each group who are exposed above the toxicity level (20 mg/L), above the therapeutic maximum (15 mg/L), and below the therapeutic minimum (2.5 mg/L) C ss steady-state concentrations should read Each column summarises the proportion of patients in each group who are exposed above the toxicity level (20 The original article can be found online at https://doi

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