Patient Adherence, More-Forgiving Antiepileptic Drugs, and Potential Impacts
Ease of administration and lower pill burdens are important factors that can aid in patient adherence. One of the most significant advances of the past few decades has been the development of antiepileptic drugs (AEDs) with long half-lives as well as extended-release (ER) formulations, both of which reduce dosing frequency.
What are the benefits of AEDs with simpler dosing and/or more-forgiving pharmacokinetic profiles (eg, in the event of a skipped/forgotten dose)?
Professor and Chief of Pediatric Neurology
“Long half-lives and ER formulations provide opportunities to better fit AED administration into a patient’s daily schedule, owing to once-daily administration. They also offer more end-of-dose forgiveness.”
Although nonadherence is the term used in the literature, we like to frame related questions in a more patient-friendly manner in practice. So, a patient is either fully adherent or partially adherent, but almost never nonadherent. Likewise, we talk about late doses, rather than skipped or missed doses. Nonetheless, nonadherence to treatment regimens can have serious or even fatal consequences for patients with epilepsy.
Ease of administration and lower pill burdens are important factors that can aid in patient adherence. One major cause of seizures among those who had been seizure free is a patient’s lateness in taking a given dose. As a result, one of the most significant advances of the past few decades has been the development of ER AED formulations and AEDs with longer half-lives than their predecessors. Long half-lives and ER formulations provide opportunities to better fit AED administration into a patient’s daily schedule, owing to once-daily administration. They also offer more end-of-dose forgiveness (ie, they remain in the patient’s system longer, offering some protection against seizures during the interval before a late dose).
When doses have been forgotten, strategies are individualized based on the AED and the patient. Patients who normally take their AED in the morning might be instructed to take it at lunch or at dinner; some ER AEDs can even be doubled up if the patient does not remember to take it until it is time for their next dose. All ER AEDs have better end-of-dose forgiveness periods than their immediate release (IR) counterparts. ER products have higher rates of seizure freedom, not only because patients are more adherent but likely also because the last portion of each dose is released relatively late after administration. Now, with agents such as perampanel that are IR but that have long half-lives, (ie, up to 105 hours), you also get that end-of-dose forgiveness.
With respect to economic and insurance issues, ER AEDs, especially branded ones, will cost more than generic IR formulations. However, sole consideration of drug costs (eg, by insurers that wish to restrict coverage) does not factor in costs saved when patients can be more adherent on these more-forgiving agents. In studies comparing ER or long half-life AEDs to IR formulations, the former actually tend to save the patient and system more money when Emergency Room visits, hospital stays, and all other consequences of epilepsy are taken into account.
“For the patient with epilepsy, 1 missed dose of an AED might result in a generalized tonic-clonic seizure that has the potential for significant risk of injury, loss of driving privileges, and other serious consequences.”
Patients with epilepsy are nonadherent for various reasons, with forgetfulness being among the most common. Patients may also make a deliberate decision not to take their medication if they are experiencing significant adverse effects, if they are experiencing issues with insurance authorization, or for any number of other reasons. For patients who require antibiotics for an infection, missing a dose usually is not a serious matter. For the patient with epilepsy, however, 1 missed dose of an AED might result in a generalized tonic-clonic seizure that has the potential for significant risk of injury, loss of driving privileges, and other serious consequences. ER formulations of AEDs have helped to reduce nonadherence. The advantage of ER formulations of levetiracetam and lamotrigine, for example, is that the patient must remember to take the medication only once daily instead of twice daily. For many patients, this is a significant benefit. However, it is also important to realize that, when agents are developed into ER formulations, the half-life of the drug remains the same as if it were IR; it is just that the last portion of that dose is released well after administration. If a patient forgets to take an ER AED, their serum level is going to fall just as quickly as if they had forgotten to take an IR formulation of the same drug, and they still risk suffering a seizure. That is why agents with longer half-lives and ER formulations are so helpful for those who may not be as punctual with their dosing; serum levels will not fall so quickly.
Professor, Department of Neurology
“Frequency, times of dosing, and side effects are all part of the patient adherence equation and factors in the individualization of treatment.”
In considering the AEDs, I would agree that the simplest treatment is potentially the more effective treatment because response to treatment depends on efficacy and also on the patient’s ability to follow through with the treatment and stay on it. Frequency, times of dosing, and side effects are all part of the patient adherence equation and factors in the individualization of treatment. Considering an AED with a longer half-life, the time to reach steady state is longer, which means a longer time before the patient reaches a stable and potentially therapeutic serum level. However, it also means that the steady state serum level is more stable once it is reached. The balance between these 2 issues of rapidity to steady state and stability of steady state can affect the choice of medication. The question becomes: How important is it to get to a stable level quickly vs how important is stability of the level if a person misses a dose? Individualization of treatment with this in mind, both in the short-term and the long-term, are important considerations.
Thinking about this issue, ER formulations and AEDs with long half-lives may be beneficial to counter the effect of normal human forgetfulness, which accounts for a large proportion of nonadherence. When individualizing the approach to a given patient, however, other factors may also be important to nonadherence and should be discussed with the patients with nonadherence. Other factors include misunderstanding of the dosing, medication cost, medication availability at the local pharmacy, concern about adverse effects, experience of adverse effects, and concern about interactions with other medications or alcohol.
Ip Q, Malone DC, Chong J, Harris RB, Labiner DM. Economic impact of epilepsy and the cost of nonadherence to antiepileptic drugs in older Medicare beneficiaries. Epilepsy Behav. 2018;80:208-214.
Modi AC, Guilfoyle SM, Mann KA, Rausch JR. A pilot randomized controlled clinical trial to improve antiepileptic drug adherence in young children with epilepsy. Epilepsia. 2016;57(3):e69-e75.
Tremblay G, Barghout V, Patel V, Tsong W, Wang Z. Budget impact of perampanel as adjunctive treatment of uncontrolled partial-onset and primary generalized tonic-clonic seizures in the United States. Epilepsy Behav. 2017;68:196-202.
Uthman BM. Extended-release antiepilepsy drugs—review of the effects of once-daily dosing on tolerability, effectiveness, adherence, quality of life, and patient preference. US Neurology. 2014;10(1):30-37.
Wheless JW, Phelps SJ. A clinician’s guide to oral extended-release drug delivery systems in epilepsy. J Pediatr Pharmacol Ther. 2018;23(4):277-292.