Tuesday, February 25, 2020

Epilepsy patients taking newer AEDs may not benefit from routine drug monitoring

Aícua-Rapún I, André P, Rossetti AO, Ryvlin P, Hottinger AF, Decosterd LA, Buclin T, Novy J. Therapeutic Drug Monitoring of Newer Antiepileptic Drugs: A Randomized Trial for Dosage Adjustment. Ann Neurol. 2020 Jan;87(1):22-29. doi:10.1002/ana.25641.


Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) is widely established for older generation AEDs, whereas there is limited evidence about newer AEDs. Our aim is to assess the benefit of TDM of newer generation AEDs in epilepsy.

We performed a randomized, controlled trial comparing systematic with rescue TDM of lamotrigine, levetiracetam, oxcarbazepine, topiramate, brivaracetam, zonisamide, or pregabalin. Participants were adults with epilepsy, in whom treatment with newer generation AEDs was initiated or needed adjustment. In the systematic TDM arm, AED plasma levels were available at each appointment, whereas in the rescue TDM arm, levels were known only if a study endpoint was reached (inefficacy or adverse events). The primary outcome was the proportion of participants followed 1 year without reaching one of the predefined endpoints.

A total of 151 participants were enrolled; global retention in the study was similar in both arms (56% overall, 58% in the systematic, and 53% in the rescue TDM arm, p = 0.6, Cox regression). There was no difference in terms of outcome regarding treatment efficacy or tolerability. Partial adherence of clinicians to TDM (adjusting or not AED dosage based on blood levels) did not explain this lack of benefit.

This study provides class A evidence that systematic drug level monitoring of newer generation AEDs does not bring tangible benefits in the management of patients with epilepsy. Poor correlation between clinical effects and drug levels likely accounts for this finding. However, TDM is useful in several situations, such as pregnancy, as well as when there are compliance issues. ANN NEUROL 2020;87:22-29.

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 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.”...

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...

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...

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...

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?”


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