Clearance rates for some antiepileptic drugs rise during pregnancy

Certain antiepileptic drugs show significant increases in clearance rates during pregnancy, which may be associated with increased seizure rates, research suggests.

Antonio_Diaz/Thinkstock

Paula E. Voinescu, MD, PhD, of Brigham and Women’s Hospital, Boston, and her coauthors conducted a prospective, observational study of 44 pregnancies in 40 women with epilepsy who were treated with antiepileptic drugs. The women were enrolled preconception or in early pregnancy, then kept daily diaries of medication doses, adherence, and seizures, while antiepileptic drug concentrations were measured every 1-3 months.

The investigators found that levetiracetam reached a mean maximal clearance during the first trimester that was 71% higher than baseline clearance (P = .0001), and its clearance level remained high throughout pregnancy.

“This is important information for clinicians who manage women on levetiracetam as they may opt to begin TDM [therapeutic drug monitoring] as early as possible in pregnancy,” the investigators wrote. The report was published online Sept. 5 in Neurology.

The authors noted that there was significant variability between participants in clearance rates of levetiracetam, ranging from 1.42-fold to 2.02-fold baseline clearance, and they suggested that pharmacogenetic differences may play a role.

“Levetiracetam is mainly excreted unchanged by the kidneys, and the changes in clearance are consistent with the time course of increased glomerular filtration rate during pregnancy,” they wrote. “The pathophysiology of the interparticipant variability in clearance fluctuation during pregnancy and of the race influence observed for levetiracetam are difficult to explain with the known pharmacokinetic data.”

Both oxcarbazepine and topiramate also reached significantly higher mean maximal clearances during the second trimester than at baseline (63% and 39% higher, respectively), and their elevated clearance persisted into the third trimester.

However, there were no significant changes in clearance rates of total or free phenytoin or valproic acid during pregnancy.

Among the 15 women for whom researchers had complete seizure history and antiepileptic drug concentrations, 40% experienced a worsening of seizure frequency during at least one trimester.

Overall, lower individualized ratio-to-target concentrations of drug were associated with increased seizure frequency in the first and second trimester, but not in the third trimester.

While the study did not compare seizure outcomes between patients who were managed with TDM and those who were not, the authors suggested that their data supported the use of TDM during pregnancy.

“The finding of lower AED RTC [antiepileptic drug ratio to concentration] at different trimesters suggests that in outpatient clinical practice, possible changes in AED dosing varied by trimester may be clinically important for patient care.”

The study was supported by the National Institutes of Health, the American Brain Foundation, the American Epilepsy Society, the Epilepsy Foundation, and the Karger Fund. Four authors declared support, honoraria, and/or other funding from the pharmaceutical industry, and five also declared support from the study funding bodies.

SOURCE: Voinescu P et al. Neurology. 2018 Sep 5. doi: 10.1212/WNL.0000000000006240.

Certain antiepileptic drugs show significant increases in clearance rates during pregnancy, which may be associated with increased seizure rates, research suggests.

Antonio_Diaz/Thinkstock

Paula E. Voinescu, MD, PhD, of Brigham and Women’s Hospital, Boston, and her coauthors conducted a prospective, observational study of 44 pregnancies in 40 women with epilepsy who were treated with antiepileptic drugs. The women were enrolled preconception or in early pregnancy, then kept daily diaries of medication doses, adherence, and seizures, while antiepileptic drug concentrations were measured every 1-3 months.

The investigators found that levetiracetam reached a mean maximal clearance during the first trimester that was 71% higher than baseline clearance (P = .0001), and its clearance level remained high throughout pregnancy.

“This is important information for clinicians who manage women on levetiracetam as they may opt to begin TDM [therapeutic drug monitoring] as early as possible in pregnancy,” the investigators wrote. The report was published online Sept. 5 in Neurology.

The authors noted that there was significant variability between participants in clearance rates of levetiracetam, ranging from 1.42-fold to 2.02-fold baseline clearance, and they suggested that pharmacogenetic differences may play a role.

“Levetiracetam is mainly excreted unchanged by the kidneys, and the changes in clearance are consistent with the time course of increased glomerular filtration rate during pregnancy,” they wrote. “The pathophysiology of the interparticipant variability in clearance fluctuation during pregnancy and of the race influence observed for levetiracetam are difficult to explain with the known pharmacokinetic data.”

Both oxcarbazepine and topiramate also reached significantly higher mean maximal clearances during the second trimester than at baseline (63% and 39% higher, respectively), and their elevated clearance persisted into the third trimester.

However, there were no significant changes in clearance rates of total or free phenytoin or valproic acid during pregnancy.

Among the 15 women for whom researchers had complete seizure history and antiepileptic drug concentrations, 40% experienced a worsening of seizure frequency during at least one trimester.

Overall, lower individualized ratio-to-target concentrations of drug were associated with increased seizure frequency in the first and second trimester, but not in the third trimester.

While the study did not compare seizure outcomes between patients who were managed with TDM and those who were not, the authors suggested that their data supported the use of TDM during pregnancy.

“The finding of lower AED RTC [antiepileptic drug ratio to concentration] at different trimesters suggests that in outpatient clinical practice, possible changes in AED dosing varied by trimester may be clinically important for patient care.”

The study was supported by the National Institutes of Health, the American Brain Foundation, the American Epilepsy Society, the Epilepsy Foundation, and the Karger Fund. Four authors declared support, honoraria, and/or other funding from the pharmaceutical industry, and five also declared support from the study funding bodies.

SOURCE: Voinescu P et al. Neurology. 2018 Sep 5. doi: 10.1212/WNL.0000000000006240.

Certain antiepileptic drugs show significant increases in clearance rates during pregnancy, which may be associated with increased seizure rates, research suggests.

Antonio_Diaz/Thinkstock

Paula E. Voinescu, MD, PhD, of Brigham and Women’s Hospital, Boston, and her coauthors conducted a prospective, observational study of 44 pregnancies in 40 women with epilepsy who were treated with antiepileptic drugs. The women were enrolled preconception or in early pregnancy, then kept daily diaries of medication doses, adherence, and seizures, while antiepileptic drug concentrations were measured every 1-3 months.

The investigators found that levetiracetam reached a mean maximal clearance during the first trimester that was 71% higher than baseline clearance (P = .0001), and its clearance level remained high throughout pregnancy.

“This is important information for clinicians who manage women on levetiracetam as they may opt to begin TDM [therapeutic drug monitoring] as early as possible in pregnancy,” the investigators wrote. The report was published online Sept. 5 in Neurology.

The authors noted that there was significant variability between participants in clearance rates of levetiracetam, ranging from 1.42-fold to 2.02-fold baseline clearance, and they suggested that pharmacogenetic differences may play a role.

“Levetiracetam is mainly excreted unchanged by the kidneys, and the changes in clearance are consistent with the time course of increased glomerular filtration rate during pregnancy,” they wrote. “The pathophysiology of the interparticipant variability in clearance fluctuation during pregnancy and of the race influence observed for levetiracetam are difficult to explain with the known pharmacokinetic data.”

Both oxcarbazepine and topiramate also reached significantly higher mean maximal clearances during the second trimester than at baseline (63% and 39% higher, respectively), and their elevated clearance persisted into the third trimester.

However, there were no significant changes in clearance rates of total or free phenytoin or valproic acid during pregnancy.

Among the 15 women for whom researchers had complete seizure history and antiepileptic drug concentrations, 40% experienced a worsening of seizure frequency during at least one trimester.

Overall, lower individualized ratio-to-target concentrations of drug were associated with increased seizure frequency in the first and second trimester, but not in the third trimester.

While the study did not compare seizure outcomes between patients who were managed with TDM and those who were not, the authors suggested that their data supported the use of TDM during pregnancy.

“The finding of lower AED RTC [antiepileptic drug ratio to concentration] at different trimesters suggests that in outpatient clinical practice, possible changes in AED dosing varied by trimester may be clinically important for patient care.”

The study was supported by the National Institutes of Health, the American Brain Foundation, the American Epilepsy Society, the Epilepsy Foundation, and the Karger Fund. Four authors declared support, honoraria, and/or other funding from the pharmaceutical industry, and five also declared support from the study funding bodies.

SOURCE: Voinescu P et al. Neurology. 2018 Sep 5. doi: 10.1212/WNL.0000000000006240.