| Description |
Epilepsy is one of the most common neurological disorders in the United States. Over the last 25 years there has been considerable development of new antiseizure drugs, however, 38% of patients on therapy still experience seizures. A contributing factor to this presentation of pharmacoresistance may be that patients don't take their medication, i.e., are nonadherent. Medication adherence is the extent to which a person takes a prescribed medication and is prerequisite to achieving efficacy with drug treatments. However, a majority of patients only take approximately half of all their prescribed medications. In patients with epilepsy, nonadherence is associated with poor seizure control and can potentially result in unwarranted, clinician directed alterations to a patient's drug regimen. Given the current setting of pervasive nonadherence, it is important to understand the consequences on seizure control. An automated drug delivery system has been previously used to model nonadherence in animals. The first pharmacokinetic characterization of this dosing system was conducted using nonlinear mixed effects modeling. Carbamazepine (CBZ), was shown to produce drug levels that are achieved and maintained within a therapeutic range when dosed using this system. Next, a preclinical model of nonadherence in rats was used to show how alterations to pharmacotherapy, made without consideration of an individual patient's adherence, results in changes to seizure control. A failure to address medication nonadherence resulted in an increase in seizures, even following a dose escalation. In contrast, the correction of nonadherence alone resulted in improved seizure control. A significant relationship was observed between a missed dose and a seizure up to five meals preceding a seizure. Additionally, it was found that simulated CBZ drug concentration was a poor predictor of seizure occurrence in the setting of nonadherence. By modeling nonadherence, we were able to directly compare 2 clinically relevant interventions at a critical decision point when ASD therapy is thought to be failing to achieve seizure control. We have established the preclinical model of nonadherence, including the pharmacokinetic validation of this model, as an important tool to isolate and study the effects of poor adherence. |
