Temporal relationship between levetiracetam nonadherence and breakthrough seizures in a preclinical model of temporal lobe epilepsy.

Abstract

Poor medication adherence remains a concern for individuals managing their epilepsy with antiseizure medicines (ASMs); however, ethical concerns around withholding medication make it impossible to study the causal relationship between missed doses and seizures in patients. Previous preclinical studies from our group suggest that mechanistically distinct ASMs have varying degrees of forgiveness when a dose is missed. However, with only a few ASMs studied in the context of nonadherence, we sought to expand on previous work to understand the relationship between levetiracetam (LEV) nonadherence and breakthrough seizures. Chronic oral dosing was initiated in rats with established epilepsy via our automated medication-in-food delivery system coupled to 24/7 video-electroencephalographic recording. Baseline seizure burden was established for 4 weeks before enrolling subjects into a 4-week treatment period with LEV in a 100% fully adherent (75 mg/kg four times daily) or 50% variably adherent paradigm. The temporal relationship between missed doses and breakthrough seizures was correlated with LEV plasma and brain concentrations in separate cohorts of animals. Full adherence to LEV significantly improved seizure control by 50% in half of the animals. Poor adherence worsened seizure frequency by 85%, with most rats having more severe seizures that formed in clusters following missed doses. LEV concentrations remained below therapeutic levels (<10 μg/mL) in nonadherent animals, with brain and plasma levels directly correlating with the degree of adherence in a 24-h period. Missed doses of LEV immediately increased the risk of breakthrough seizures; however, this risk was significantly reduced with improved adherence in a 24-h period. These findings enhance our understanding of ASM nonadherence in preclinical models, highlighting that the timing of missed doses and their impact on seizures may vary between different ASMs. Notably, LEV demonstrates a robust pharmacokinetic reliance on missed doses leading to breakthrough seizures.