P Emanuela Voinescu1, Suna Park1, Li Q Chen1, Zachary N Stowe1, D Jeffrey Newport1, James C Ritchie1, Page B Pennell2. 1. From Brigham and Women's Hospital (P.E.V., L.Q.C., P.B.P.), Harvard Medical School; Harvard Chan School of Public Health (S.P.), Boston, MA; University of Wisconsin School of Medicine and Public Health (Z.N.S.), Madison; University of Miami Miller School of Medicine (D.J.N.), FL; and Emory University School of Medicine (J.C.R.), Atlanta, GA. 2. From Brigham and Women's Hospital (P.E.V., L.Q.C., P.B.P.), Harvard Medical School; Harvard Chan School of Public Health (S.P.), Boston, MA; University of Wisconsin School of Medicine and Public Health (Z.N.S.), Madison; University of Miami Miller School of Medicine (D.J.N.), FL; and Emory University School of Medicine (J.C.R.), Atlanta, GA. ppennell@bwh.harvard.edu.
Abstract
OBJECTIVE: To characterize the magnitude and time course of pregnancy-related clearance changes for different antiepileptic drugs (AEDs): levetiracetam, oxcarbazepine, topiramate, phenytoin, and valproate. A secondary aim was to determine if a decreased AED serum concentration was associated with increased seizure frequency. METHODS: Women with epilepsy were enrolled preconception or early in pregnancy and prospectively followed throughout pregnancy and the first postpartum year with daily diaries of AED doses, adherence, and seizures. Study visits with AED concentration measurements occurred every 1-3 months. AED clearances in each trimester were compared to nonpregnant baseline using a mixed linear regression model, with adjustments for age, race, and hours postdose. In women on monotherapy, 2-sample t test was used to compare the ratio to target concentrations (RTC) between women with seizure worsening each trimester and those without. RESULTS: AED clearances were calculated for levetiracetam (n = 18 pregnancies), oxcarbazepine (n = 4), topiramate (n = 10), valproate (n = 5), and phenytoin (n = 7). Mean maximal clearances were reached for (1) levetiracetam in first trimester (1.71-fold baseline clearance) (p = 0.0001), (2) oxcarbazepine in second trimester (1.63-fold) (p = 0.0001), and (3) topiramate in second trimester (1.39-fold) (p = 0.025). In 15 women on AED monotherapy, increased seizure frequency in the first, second, and all trimesters was associated with a lower RTC (p < 0.05). CONCLUSION: AED clearance significantly changes by the first trimester for levetiracetam and by the second trimester for oxcarbazepine and topiramate. Lower RTC was associated with seizure worsening. Early therapeutic drug monitoring and dose adjustment may be helpful to avoid increased seizure frequency.
OBJECTIVE: To characterize the magnitude and time course of pregnancy-related clearance changes for different antiepileptic drugs (AEDs): levetiracetam, oxcarbazepine, topiramate, phenytoin, and valproate. A secondary aim was to determine if a decreased AED serum concentration was associated with increased seizure frequency. METHODS: Women with epilepsy were enrolled preconception or early in pregnancy and prospectively followed throughout pregnancy and the first postpartum year with daily diaries of AED doses, adherence, and seizures. Study visits with AED concentration measurements occurred every 1-3 months. AED clearances in each trimester were compared to nonpregnant baseline using a mixed linear regression model, with adjustments for age, race, and hours postdose. In women on monotherapy, 2-sample t test was used to compare the ratio to target concentrations (RTC) between women with seizure worsening each trimester and those without. RESULTS: AED clearances were calculated for levetiracetam (n = 18 pregnancies), oxcarbazepine (n = 4), topiramate (n = 10), valproate (n = 5), and phenytoin (n = 7). Mean maximal clearances were reached for (1) levetiracetam in first trimester (1.71-fold baseline clearance) (p = 0.0001), (2) oxcarbazepine in second trimester (1.63-fold) (p = 0.0001), and (3) topiramate in second trimester (1.39-fold) (p = 0.025). In 15 women on AED monotherapy, increased seizure frequency in the first, second, and all trimesters was associated with a lower RTC (p < 0.05). CONCLUSION: AED clearance significantly changes by the first trimester for levetiracetam and by the second trimester for oxcarbazepine and topiramate. Lower RTC was associated with seizure worsening. Early therapeutic drug monitoring and dose adjustment may be helpful to avoid increased seizure frequency.
Authors: Andreas Austgulen Westin; Karl Otto Nakken; Svein I Johannessen; Arne Reimers; Kari Mette Lillestølen; Eylert Brodtkorb Journal: Epilepsia Date: 2008-10-30 Impact factor: 5.864
Authors: Ellen Mawhinney; John Craig; Jim Morrow; Aline Russell; W Henry Smithson; Linda Parsons; Patrick J Morrison; Brenda Liggan; Beth Irwin; Norman Delanty; Stephen J Hunt Journal: Neurology Date: 2013-01-09 Impact factor: 9.910
Authors: Andreas Austgulen Westin; Arne Reimers; Grethe Helde; Karl Otto Nakken; Eylert Brodtkorb Journal: Seizure Date: 2008-01-03 Impact factor: 3.184
Authors: P Emanuela Voinescu; Kurt D Pennell; Camden P Bay; Zachary N Stowe; Limin Peng; Cheryl A Frye; Kathleen Y Tang; Page B Pennell Journal: Epilepsy Res Date: 2021-09-25 Impact factor: 3.045
Authors: Angela K Birnbaum; Kimford J Meador; Ashwin Karanam; Carrie Brown; Ryan C May; Elizabeth E Gerard; Evan R Gedzelman; Patricia E Penovich; Laura A Kalayjian; Jennifer Cavitt; Alison M Pack; John W Miller; Zachary N Stowe; Page B Pennell Journal: JAMA Neurol Date: 2020-04-01 Impact factor: 18.302
Authors: Page B Pennell; Jacqueline A French; Ryan C May; Elizabeth Gerard; Laura Kalayjian; Patricia Penovich; Evan Gedzelman; Jennifer Cavitt; Sean Hwang; Alison M Pack; Maria Sam; John W Miller; Steffanie H Wilson; Carrie Brown; Angela K Birnbaum; Kimford J Meador Journal: N Engl J Med Date: 2020-12-24 Impact factor: 91.245