Extended-release formulations for the treatment of epilepsy

Abstract

This review analyses the concept of extended-release (ER) formulations in epilepsy and evaluates ER formulations of carbamazepine, valproic acid and a modified-release (MR) formulation of oxcarbazepine. ER formulations are usually designed to reduce dose frequency and maintain relatively constant or flat plasma drug concentration. It is questionable whether flat plasma concentrations of an antiepileptic drug (AED) improve antiepileptic efficacy compared with fluctuating plasma concentrations. More certainly, they minimise concentration-related adverse effects, and the dosing flexibility and consistency of plasma concentrations may simplify the management of antiepileptic drug therapy. Neurologists would like ER formulations that can be administered once- and/or twice-daily to tailor therapy for the individual patient; however, switching dosage schedules from multiple dosages per day to once daily, although more convenient, will not generally improve therapeutic coverage (maintenance of effective drug concentration in biological fluids and tissue). Pharmacokinetically, the impact of a missed dose is greater the larger the dose and the less frequent the administration. Therefore, the risk of breakthrough seizure is higher during AED once-daily administration than twice-daily administration. Consequently, the increased compliance observed with fewer dosages per day should be weighed against the impact or forgiveness of omitted dose(s) and the shorter 'forgiveness' period associated with once-daily administration. Currently, the trend is to treat patients with epilepsy with ER formulations because of the better compliance, convenience and flat plasma concentration versus time curve. Thus, it seems that the term 'flatter is better' for AED plasma profiles has precipitated in the last 10-15 years among neurologists and epilepsy caregivers, and is being promoted by marketing forces of pharmaceutical companies. Data from the literature support the trend to treat epileptic patients with twice-daily administration of the existing ER formulations of valproic acid and carbamazepine, and oxcarbazepine-MR; however, the author of this article is not convinced that these ER formulations can guarantee a complete therapeutic coverage throughout the 24-hour dosing interval following once-daily administration. Epilepsy is a single-episode disease, and the convenience and possible better compliance associated with once-daily administration must be weighed against the shorter 'forgiveness' period and possible higher risk of breakthrough seizure due to sub-therapeutic plasma levels and/or omitted doses. Data suggest just a small difference in compliance between once- and twice-daily administration, with no significant difference in efficacy. Therefore, the increased compliance following once-daily administration may be counter-productive in minimising the occurrence of sub-therapeutic drug concentrations. Weighing up the advantages and disadvantages for once- versus twice-daily administration of ER formulations in epilepsy leads to a conclusion in favour of twice-daily administration.