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.
Abstract
OBJECTIVE:
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.
METHODS:
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.
RESULTS:
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.
INTERPRETATION:
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?”
https://journals.lww.com/neurotodayonline/Fulltext/2020/02060/Epilepsy_Patients_Taking_Newer_AEDs_May_Not.1.aspx
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