Extended-release antiepileptic drugs: A comparison of pharmacokinetic parameters relative to original immediate-release formulations

Many antiepileptic drugs (AEDs) have short half-lives with large fluctuations in peak-to-trough plasma concentrations. Consequences of these pharmacokinetic (PK) properties may include adverse events (AEs) and breakthrough seizures, potentially leading to poor adherence. To address these challenges, newer formulations of these AEDs have been developed using unique extended-release (ER) technologies. These technologies extend the dosing interval such that dosing frequency can be minimized, which may improve patient adherence. Available ER formulations have the potential to minimize the spikes in maximum plasma concentrations (C_max) at steady-state that often contribute to AEs during treatment with immediate-release (IR) products. In so doing, tolerability advantages may lead to increased AED effectiveness by improving adherence and allowing higher doses if clinically indicated. Direct PK comparison studies of IR and ER formulations (e.g., carbamazepine, divalproate sodium, lamotrigine, oxcarbazepine, levetiracetam, and phenytoin) have found that dose-normalized ER formulations may or may not be bioequivalent to their IR counterparts, but most ER formulations have a lower fluctuation index ([C _max-C_min]/C_avg) compared with the IR versions. This results in flatter concentration-time plots. Not all ER preparations improve the various PK parameters to the same extent, and PK nuances may impact the effectiveness, tolerability, and adherence rates of various ER formulations.