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Epilepsy Patients Taking Newer AEDs May Not Benefit from Routine Drug Monitoring

Article In Brief

Investigators found no notable difference in seizure control between patients whose blood levels of antiepileptic drugs were monitored and those whose levels were not monitored.

Doing routine monitoring of drug levels of the newer antiepileptic drugs (AEDs) may not lead to better seizure control or treatment tolerance for patients with epilepsy, according to a randomized trial from Switzerland.

The trial compared a group of patients whose doctors knew the results of their patient's systematic therapeutic drug monitoring with a group of patients whose blood test results were not revealed to the treating physician. The investigators found no notable difference between the two groups when it came to seizure control and adverse events over the length of the study, which was published in the January issue of Annals of Neurology.

“The main finding is that despite the variable bioavailability of the newer- generation AEDs, the systematic monitoring of their plasma levels does not bring a tangible benefit for patients,” said Jan Novy, MD, PhD, the study supervisor, neurologist, and senior lecturer at the University of Lausanne.

However, therapeutic drug monitoring of the newer AEDs is advisable in certain situations, such as when the patient is pregnant or there is a suspicion the patient is not taking the medication as prescribed, Dr. Novy told Neurology Today in an interview.

The question of whether therapeutic drug monitoring of newer AEDs is justified has been debated in part because routine monitoring was done for older-generation AEDs, including phenytoin, carbamazepine, phenobarbital, and valproate, and some clinicians have just continued the habit.

“The relationship between AED plasma levels and clinical effect has been well established for those agents, allowing the definition of reference ranges that are widely accepted,” the paper said.

Newer-generation AEDs, in comparison, have much broader therapeutic ranges, and there is not as much clear evidence of a correlation between plasma levels of the drug and clinical response, according to the new paper.

The utility of therapeutic drug monitoring for newer AEDs was never assessed in a controlled trial, the study authors wrote, adding: “Its usefulness tends, however, to be accepted and even recommended for certain situations such as pregnancy.”

Study Design, Findings

The trial enrolled 151 patients between June 2016 and December 2017. Half were assigned to systematic therapeutic drug monitoring and the other half to what was called “rescue” drug monitoring (in which results were only revealed if there was a treatment failure). The participants were older than 18, diagnosed with epilepsy, and followed in an outpatient clinic. Pregnant women were excluded. Most of the participants (75.5 percent) had focal epilepsy and half had drug-resistant epilepsy. They were all taking a newer-generation AEDs, most commonly lamotrigine (66 participants) and levetiracetam (31), followed by zonisamide, topiramate, lacosamide, and oxcarbazepine. Half of the study participants were treated with monotherapy.

Of the 151 patients who participated in the study, 87 were enrolled because of dosage adjustments and 64 because of the introduction of a new AED, of which 17 patients were drug naïve.

Patients were followed for one year, with checkups about three or four times during the year. Participants in each arm had their blood drawn at each clinical visit, but the test results were only communicated to the doctors whose patients were in the systematic arm. The doctors were free to act on the blood level readings as they chose.

In the “rescue” therapeutic drug monitoring arm, physicians were blinded to blood test results only until there was a treatment failure as defined by the study. The combined endpoint (representing treatment failure) was defined by any of the following: two or more seizures with impaired awareness (with or without generalized tonic-clonic seizures), status epilepticus (defined as any seizure lasting more than five minutes), need of an add-on AED, or need to discontinue the studied drug (whether for lack of efficacy or adverse reaction).

Global retention for the study was 56 percent, meaning 69 of 151 patients made it to the one-year mark without reaching an endpoint. Retention in the systematic arm was 58 percent compared with 53 percent in the rescue arm.

Figure

“The main finding is that despite the variable bioavailability of the newer-generation AEDs, the systematic monitoring of their plasma levels does not bring a tangible benefit for patients.”—DR. JAN NOVY

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“Although there are general therapeutic guidelines (for AEDs), different patients respond differently. With that in mind, I am more interested in an individual response to an individual dose.”—DR. SHAWNIQUA ROBERSON WILLIAMS

During the study, 43 dose adjustments were prescribed to 32 patients undergoing systematic drug monitoring compared with 38 adjustments to 31 patients in the blinded arm.

“There was no difference in terms of outcome regarding treatment efficacy or tolerability,” the study reported.

“These results suggest that continuously monitoring drug levels provides at most a modest benefit in the outcome of patients with epilepsy,” the researchers concluded.

The study authors cautioned that despite that general conclusion, systematic monitoring is warranted for pregnant women, as well as cases where compliance is an issue, the patient has renal or hepatic dysfunction, or there is possible drug interaction.

The authors also noted limitations of the study, including its relatively small size, and the fact that blood draws were not necessarily taken at an ideal time for drug monitoring. (Levels were interpreted by a pharmacist.) Endpoints used for the study were also very stringent compared to those used in previous trials. The patients were seen in an epilepsy clinic, which may not represent the broader array of clinical settings.

Dr. Novy said there were also some potential downsides to unnecessary monitoring not discussed in the paper including costs, inconvenience for the patient, and perhaps over-management of patients based on blood test results rather than clinical observations.

“It is, for instance, not uncommon to see a general practitioner decrease the dosage of a medication (typically levetiracetam) because its plasma level is above the reference range, while the patent has no sign of toxicity,” Dr. Novy said.

Expert Commentary

Shawniqua Williams Roberson, MD, assistant professor of neurology at Vanderbilt University Medical Center, said the study findings fit with her clinical practice, noting “I don't think that getting levels systematically every three months is useful.”

Dr. Williams Roberson said she does tend to get a blood reading if a patient changes doses or starts a new drug or if she suspects the patient is noncompliant. But she considers the blood level to be a baseline number that can serve as a reference point going forward if there is a need to switch drugs or dosage due to clinical symptoms rather.

Dr. Williams Roberson said most new AEDs have very broad therapeutic ranges and a dosage that might work for one patient may not work for another.

“Although there are general therapeutic guidelines (for AEDs), different patients respond differently,” Dr. Williams Roberson said. “With that in mind, I am more interested in an individual response to an individual dose.” She said putting too much emphasis on blood levels could mean “unnecessarily adjusting a dose based on what the blood level comes out to be.” She prefers to take time to see how a patient responds and adjusts to a given dose or drug.

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“The study confirms the general clinical practice impression that the usefulness of getting drug levels on the newer AEDs is limited when you compare a patient against the general population, especially given the broad therapeutic ranges of the newer AEDs, which are so broad as to be virtually meaningless.”—DR. PAVEL KLEIN

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“I may have one patient who at 2.5 (mg/L) of lamotrigine is seizure free, but another patient may need a level of 6 to 8. The driving principle needs to be what is right for this patient?”—DR. PAGE B. PENNELL

“I like to tell my patients, ‘I prefer to treat the patient, not the number,’” Dr. Williams Roberson said.

Pavel Klein, MD, FAAN, founder and director of the Mid-Atlantic Epilepsy Center In Bethesda, MD, said the new study echoes an epilepsy treatment mantra he learned in residency that “you treat the patient, not blood levels.”

“The study confirms the general clinical practice impression that usefulness of getting drug levels on the newer AEDs is limited when you compare a patient against the general population, especially given the broad therapeutic ranges of the newer AEDs, which are so broad as to be virtually meaningless.”

He said the new AEDs are not like the blood-thinning drug warfarin, for instance, where having too little or too much of the drug circulating in the body can be dangerous.

But Dr. Klein cautioned against drawing sweeping conclusions about the new study because most of the study participants were taking just one of two AEDs, lamotrigine and levetiracetam, and several newer AEDs were not evaluated at all.

He said he finds that getting a baseline reading on an AED can be revealing if it is used to “compare a patient to him or herself” should there be a change in how a patient is faring. Getting a blood level can also be useful in the case of medication non-compliance or to check for possible drug interactions if a patient is taking a number of different drugs for various conditions, he said.

Dr. Klein said he'd be interested in seeing a study that would evaluate the usefulness of doing therapeutic drug monitoring of a patients' AED levels longitudinally to see how they correlate with the patient's clinical status. Some insight into dosing might be learned from such a study, he said.

Page B. Pennell, MD, professor of neurology at Harvard Medical School and director of epilepsy research at Brigham and Women's Hospital, said that while she generally agreed with the overall study findings, “I hope people, don't throw out the baby with the bath water.”

Dr. Pennell specializes in women with epilepsy who are pregnant or wanting to become pregnant and said that in those cases getting the patient's AED blood level does have value in helping determine optimal treatment. She said oral contraceptives can also influence AED drug levels, so getting a baseline reading can likewise be informative.

Another instance where she likes getting a baseline reading is with older people with late-onset epilepsy, defined as over the age of 50 or 60. She said those older patients might require a much lower dose of drug and yet they may have higher circulating levels of the drug than would be expected.

Dr. Pennell said that while doctors draw on their collective clinical experience in making prescribing decisions, it's important to consider each patient as an individual.

“I may have one patient who at 2.5 (mg/L) of lamotrigine is seizure free, but another patient may need a level of 6 to 8,” she said. “The driving principle needs to be what is right for this patient?”

Disclosures

Drs. Novy, Roberson Williams, and Pennell had no competing interests.

Link Up for More Information

• Aicua-Rapun I, Andre P, Rossetti AO, et al. Therapeutic drug monitoring of newer antiepileptic drugs: A randomized trial for dosage adjustment https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.25641. Ann Neurol 2020;87(1):22–29.