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5 Common AEDs: Their Drug Clearance and Risk for Seizures During Pregnancy

ARTICLE IN BRIEF

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INCREASED SEIZURE FREQUENCY in the first and second trimester, and for the entire pregnancy, was associated with a lower ratio-to-concentration of antiepileptic drugs.

A new analysis provides data on drug clearance and the risk for breakthrough seizures during pregnancy for these five antiepileptic drugs: levetiracetam, oxcarbazepine, topiramate, phenytoin, and valproic acid.

During pregnancy, the clearance of many antiepileptic drugs (AEDs) increases significantly, resulting in diminishing ratio-to-target concentrations (RTC) and associated seizure worsening, according to an August 29 online report in Neurology.

Average maximal clearance was reached for levetiracetam in the first trimester, and for oxcarbazepine and topiramate in the second trimester. Increased seizure frequency in the first and second trimester, and for the entire pregnancy, was associated with a lower RTC of antiepileptic drugs.

The findings appear to be most striking for levetiracetam. “Data on the relative safety of levetiracetam during pregnancy has made it a drug of first choice for women with epilepsy who are planning to become pregnant,” said principal investigator Page B. Pennell, MD, professor of neurology at Harvard Medical School and director of research in the division of epilepsy at Brigham and Women's Hospital. The first author on the study was Paula Emanuela Voinescu, MD, PhD, of the department of neurology at Brigham and Women's Hospital.

“What our study shows is that clearance of levetiracetam increases markedly during pregnancy as early as the first trimester, long before women have significant weight gain,” Dr. Pennell told Neurology Today. “We also show that a decrease in drug concentration to less than 65 percent of the target is associated with breakthrough seizures. We believe this further supports the establishment of a target concentration prior to pregnancy and drug monitoring throughout the pregnancy.”

She added that some recent European studies are showing oxcarbazepine to be safe for use in pregnancy, so its use may become more common.

STUDY DETAILS

Dr. Pennell and colleagues enrolled women with epilepsy who were planning to conceive or at less than 16-weeks gestational age (GA) presenting at the Emory Clinic between December 2002 and November 2007. The women were followed throughout pregnancy and the first postpartum year with daily diaries of AED doses, adherence, and seizures.

The investigators calculated drug clearances in a total of 44 women in these AEDs: levetiracetam (n=18 pregnancies), oxcarbazepine (n=4), topiramate (n=10), valproate (n=5), and phenytoin (n=7). AED clearances in each trimester were compared to the non-pregnant baseline. In women on monotherapy, they did a statistical analysis to compare the RTC between women with seizure worsening each trimester and those without. (RTC was calculated as average serum AED concentration in each trimester divided by average serum AED concentration in the non-pregnant baseline.)

The analysis of seizure frequency in women on monotherapy included a seizure history beginning one year prior to pregnancy through to the end of pregnancy. To calculate seizure frequency, the total number of seizures (all types) were divided by number of weeks in respective periods of time.

They found that peak clearance for levetiracetam occurs in the first trimester at 1.71 times the baseline clearance. Significant clearance changes were also noted for oxcarbazepine and topiramate, with a peak in the second trimester to 1.63 times the baseline for oxcarbazepine and 1.39-times the baseline for topiramate. These increased values persisted in the third trimester. No significant changes in clearance occurred for total or free phenytoin or valproic acid.

Seizure frequency worsened in six of 15 women on monotherapy (40 percent) during at least one trimester. Increased seizure frequency was associated with a lower RTC in the first trimester and second trimester, and for the entire pregnancy, but not for the third trimester. Additionally, an RTC of less than 0.65 was associated with seizure worsening; an RTC greater than 0.65 was associated with stable and improved seizure frequency.

Dr. Pennell said establishing a target concentration prior to pregnancy, when that is possible, is an aspect of “personalized medicine” critical to the health of mothers with epilepsy and their fetus. “Ideally, women should go into the pregnancy with a target concentration to maintain,” she told Neurology Today.

During pregnancy, she said, monthly AED levels should be obtained for therapeutic drug monitoring to maintain the nonpregnant individual target concentration. Doses should be adjusted for seizures, side effects, and to prevent the RTC from decreasing to 65 percent or lower.

EXPERT COMMENTS

Experts who reviewed the report for Neurology Today agreed the study contributes vital information about a topic of importance to women with epilepsy, and lends support to recommendations for therapeutic drug monitoring during pregnancy.

“This is an important and well-designed study of the effects of pregnancy on the clearance of five commonly-taken antiepileptic drugs (AEDs) and the associated occurrence of seizures,” Steven C. Schachter, MD, FAAN, professor of neurology at Harvard Medical School and a past president of the American Epilepsy Society, said. “The findings are relevant to physicians caring for pregnant women with epilepsy to minimize the possibility of breakthrough seizures, which could have an adverse impact on both the mother and the fetus.

“The numbers of women treated with each AED were relatively low, and yet the effects of pregnancy on drug clearance were strong enough to be statistically significant, which is impressive,” Dr. Schachter said. (Dr. Schachter is working with a start-up company that is developing a fingerstick test to measure AED levels.)

He noted especially the variability of timing of clearance for the different AEDs. “Physicians should take heed and increase their monitoring of AED serum levels in light of the results so that appropriate changes in AED dosages can be made before, during, and after pregnancy,” he told Neurology Today.

Kimford J. Meador, MD, FAAN, professor of neurology at Stanford University, agreed. “Clearance is increased during pregnancy for some AED drugs, but that clearance is variable across women, so it is hard to predict,” he said. “Clinicians should be aware of these potential changes and monitor for changes in AED levels during pregnancy since reduction in AED levels can lead to breakthrough seizures.”

Jacqueline A. French, MD, FAAN, professor at the NYU Comprehensive Epilepsy Center, said the need for therapeutic drug monitoring during pregnancy has been a subject of debate. But she said it is now well established that monitoring of serum concentrations is warranted for women taking lamotrigine, and prospective studies have demonstrated that if levels fall to less than 65 percent of baseline levels, women will be at risk for seizures.

“The current paper now expands these findings to levetiracetam, a drug very commonly used in pregnancy, as well as oxcarbazepine and topiramate,” Dr. French said. “Physicians caring for women with epilepsy should obtain a pre-pregnancy baseline serum concentration on women of childbearing age, obtain another serum concentration as early as possible once pregnancy has been confirmed, and continue to monitor blood levels throughout the pregnancy. If levels fall, dose adjustments should be made.”

DISCLOSURES

Dr. Pennell disclosed no conflicts. Dr. Meador has consulted for the Epilepsy Study Consortium for the following companies: Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals. In addition, he is co-investigator and director of Cognitive Core of the Human Epilepsy Project for the Epilepsy Study Consortium, which pays Dr. Meador's university for his time as core director, co-investigator, and consultant work. Dr. Schachter has received a stipend as an advisor to Biscayne Neurotherapeutics and has received royalty payments from Elsevier, UpToDate, and several other publishers. Dr. French serves on the editorial board of Neurology Today.

LINK UP FOR MORE INFORMATION:

• Voinescu PE, Park S, Chen LQ, et al. Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy http://n.neurology.org/lookup/doi/10.1212/WNL.0000000000006240. Neurology 2018; Epub 2018 Sep 5..