WASHINGTON, DC—The efficacy and tolerability of an antiepileptic drug (AED) depend on its dose, formulation, and route of delivery, according to an overview presented at the 67th Annual Meeting of the American Epilepsy Society. For optimal outcomes, these three factors should be personalized according to the clinical situation and the individual patient’s characteristics, said Emilio Perucca, MD, PhD.
In terms of pharmacokinetics, “generally speaking, flatter is better, meaning that producing steady, sustained, stable AED concentrations in the blood, and therefore in the brain, is considered to be in most cases the ideal situation in epilepsy treatment,” said Dr. Perucca, Professor of Pharmacology at the University of Pavia in Italy. For most patients, seizures can occur at any time of the day, “so if we maintain a therapeutic concentration that does not exceed the threshold above which side effects occur throughout 24 hours, we are in the best situation to treat the patient,” he added.
Do Sustained-Release Formulations Improve Outcome?
For any AED, the minimal concentration required for seizure control and the threshold concentration for toxicity may differ from patient to patient. For some drugs with short half-lives, using an immediate-release formulation once or twice daily can produce high concentrations at the time of peak, thus increasing the risk of side effects. At the time of trough, drug concentration may fall below the level required for efficacy, thus creating the potential for breakthrough seizures.
For such drugs, a sustained-release formulation administered once or twice daily may be a better option because it reduces the fluctuation in serum blood levels, said Dr. Perucca. And evidence indicates that compliance generally is better when a drug is taken once or twice daily than when it is taken three or four times daily. But for the majority of AEDs, the literature does not include strong evidence that a sustained-release formulation administered once or twice daily improves outcome, compared with an immediate-release formulation.
One exception is carbamazepine, which was examined in a double-blind, randomized controlled study comparing an immediate-release with a sustained release formulation in 48 patients with seizures or intermittent side effects. Under double-blind conditions, physicians attempted to optimize patients’ doses and minimize dosing frequency. After dose optimization, patients underwent one month of evaluation. The controlled-release formulation of carbamazepine greatly reduced the percentage of patients with intermittent side effects. The formulation also reduced monthly seizure frequency and the number of patients who required three or four daily doses.
Two studies of elderly patients with new-onset epilepsy also produced results consistent with improved tolerability of sustained-release carbamazepine. In the first study, 150 patients were randomized to receive lamotrigine or immediate-release carbamazepine. They were followed up for 20 weeks, and the primary outcome was the number of patients who remained on the allocated treatment. Almost twice as many patients remained on lamotrigine as remained on carbamazepine. The second study used the same protocol but substituted sustained-release carbamazepine for immediate-release carbamazepine. The researchers ultimately found virtually no difference between the lamotrigine and the sustained-release carbamazepine groups in the number of patients remaining on therapy.
Sustained-release formulations do entail concerns, however. They may not have the same bioavailability as immediate-release formulations. Moreover, forgetting to take a once-daily sustained-release dose could pose greater risks than forgetting to take one of three immediate-release doses. Also, sustained-release formulations tend to cost more than immediate-release formulations, said Dr. Perucca.
Flatter May Not Always Be Better
Neurologists may not always want a patient to maintain flat serum levels of an AED. For example, the serum concentration of a drug with a wide therapeutic index may fluctuate widely, especially in an immediate release formulation, but they may still remain in the therapeutic range without causing peak-concentration side effects. This could be true for wide therapeutic index AEDs such as levetiracetam, for example, although formal studies investigating the clinical implications of daily fluctuations in serum levetiracetam levels have not been conducted yet, said Dr. Perucca.
If a patient’s seizures tend to occur at a particular time of day, a neurologist may choose to give the patient a higher dose of AED before that time. Few studies have examined this approach, but some data are available. One retrospective analysis examined 17 children with uncontrolled nocturnal and early morning seizures who were switched to proportionally higher evening doses of their AEDs without changing their daily doses. At follow-up, 11 children had become seizure-free, and four children had a major reduction in seizure frequency.
Nonoral Administration May Be Indicated
Although AEDs are most often given orally, neurologists may need to consider other routes of administration for certain patients, particularly in the emergency setting. An unconscious or vomiting patient, for example, may be unable to take oral medications, and a parenteral route of administration may be advantageous in this situation. Many studies have examined nonoral routes of administration for emergency treatment.