Abstracts

Rationale: Plasma protein binding, and its effects on volume of distribution and pharmacologically active circulating drug concentrations, is a complex issue in pharmacokinetics. In addition, protein binding displacement is a commonly cited mechanism for clinically meaningful drug-drug interactions. Perampanel, a selective non-competitive AMPA receptor antagonist, is approved in over 40 countries for adjunctive treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged ≥12 years (Canada ≥18 years). Perampanel has a low-extraction ratio and is extensively metabolized via cytochrome P450 3A4, with an elimination half life of approximately 100 hours. Since perampanel is also extensively bound to serum albumin (>95%), we conducted in vitro analyses to evaluate: (1) the potential for perampanel to act as a displacer, and (2) the displacement of perampanel by other commonly used anti-epileptic drugs (phenytoin or valproate) or a highly bound reference drug (warfarin).Methods: Plasma protein binding of perampanel, phenytoin, valproate and warfarin (racemic) was assessed using an equilibrium dialysis method. Plasma samples containing a range of clinically relevant concentrations of each drug were dialyzed against phosphate buffered saline (pH 7.4) at 37°C for 24 hours. Samples were prepared in triplicate for each assessed concentration. For phenytoin, valproate, and warfarin, plasma samples were also dialyzed in the presence of perampanel (n=3 per sample). After a 24-hour equilibrium dialysis, amounts of test articles in samples were analyzed by liquid chromatography-tandem mass spectrometry.Results: At all clinically relevant concentrations, there was no evidence that perampanel was a displacer of phenytoin, valproate or warfarin (Table 1), or that perampanel was displaced by phenytoin, valproate or warfarin (Table 2).Conclusions: Protein binding displacement has the potential to be a confounder in the interpretation of therapeutic drug monitoring of commonly used medications in patients with epilepsy. Specifically, clinicians may be concerned that co-administration of perampanel could result in alterations in unbound concentrations of other medications, leading to adverse effects. However, data presented here indicate that drug-drug interactions resulting from protein binding displacement are unlikely with perampanel. Funding: This study was funded by Eisai Co. Ltd.