Correction of medication nonadherence results in better seizure outcomes than dose escalation in a novel preclinical epilepsy model of adherence

Abstract

Summary Objective Medication nonadherence directly contributes to poor seizure control. A lack of emphasis on correcting poor adherence and failures in patient adherence can result in unwarranted alterations to a patient's drug regimen. We have modeled nonadherent patients in an animal model of epilepsy to study how alterations to pharmacotherapy, made without consideration of a patient's adherence, result in changes to seizure control. Methods Newly diagnosed rats with epilepsy were treated with carbamazepine (CBZ) during a 4‐week baseline period to establish their baseline seizure rate in the presence of 50% adherence. Next, animals were randomized to one of three treatment interventions and monitored for 6 weeks. Groups included: (1) no change in therapy—rats continued the 50% adherent paradigm; (2) dose escalation—the dose of CBZ was doubled, and the 50% adherent paradigm continued; and (3) nonadherence corrected—rats continued the initial dose of CBZ, but the adherence rate was adjusted to 100% (ie, fully adherent). Results The rats in the no change in therapy arm displayed a 61% increase in seizure burden over the 6‐week intervention phase. Similarly, rats in the dose escalation arm had a 66% worsening of their daily seizure burden. In contrast, rats in the nonadherence corrected arm displayed a 33% reduction in their daily seizure burden; a significant improvement when compared to the normalized seizure burden scores of rats in the other two treatment arms (P < 0.01). Significance We found that failure to correct medication nonadherence resulted in an increase in daily seizure burden in rats, even following dose escalation. In the presence of nonadherence, dose escalation worsened seizure control. In contrast, correcting nonadherence alone resulted in improved seizure control. These findings suggest that improving adherence should be prioritized over dose escalation in the clinical management of uncontrolled epilepsy.

The pharmacokinetics of oral carbamazepine in rats dosed using an automated drug delivery system

“…This drug delivery system directly addresses these issues by achieving an easy to use automated system for the chronic delivery of drugs. To date, two preclinical reverse translational studies have been conducted that dosed CBZ, four times daily for 6 weeks and 10 weeks; thus longer trials can easily be accomplished using this system. Not only is chronic administration important, but it is crucial to maintain therapeutic concentrations throughout the study period.…”

“…for 10 days. The daily dose of 300 mg/kg was chosen as it has been shown to be effective at reducing seizure frequency in rats with acquired epilepsy using an animal model of medial temporal lobe epilepsy and to achieve therapeutic concentrations acutely, following once per day dosing …”

“…An automated drug delivery system has been used to accomplish a clinically relevant dosing regimen of the antiseizure drug (ASD) carbamazepine (CBZ) to rats . The system delivers CBZ formulated in food pellets at a user defined rate (eg, every 4 hours).…”

“…An automated drug delivery system has been used to accomplish a clinically relevant dosing regimen of the antiseizure drug (ASD) carbamazepine (CBZ) to rats. [4][5][6] The system delivers CBZ formulated in food pellets at a user defined rate (eg, every 4 hours). This better represents the clinical treatment of epilepsy, where patients receive long-term therapy with oral medications administered multiple times per day.…”

Clinical Pharmacists in Chronic Care

“…Medication nonadherence directly contributes to poor seizure control. A lack of emphasis on correcting poor adherence and failures in patient adherence can result in unwarranted alterations to a patient's drug regimen [252]. Timely recognition and effective early therapy with first-and second-line antiepileptic drugs (AEDs) may avert unnecessary hospitalizations.…”