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Published online before print November 28, 2007, doi:10.1212/01.wnl.0000289511.20864.2a)
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NEUROLOGY 2008;70:2130-2136
© 2008 American Academy of Neurology

Lamotrigine in pregnancy

Clearance, therapeutic drug monitoring, and seizure frequency

P. B. Pennell, MD, L. Peng, PhD, D. J. Newport, MD, J. C. Ritchie, PhD, A. Koganti, MD, D. K. Holley, BA, M. Newman, RN and Z. N. Stowe, MD

From the Emory Epilepsy Program, Department of Psychiatry and Behavioral Sciences (D.J.N.), Department of Pathology (J.C.R.), Department of Neurology (P.B.P., A.K., D.K.H., M.N.), and Departments of Psychiatry and Behavioral Sciences and of Gynecology and Obstetrics (Z.N.S.), Emory University School of Medicine; and Department of Biostatistics, Rollins School of Public Health, Emory University (L.P.), Atlanta, GA.

Address correspondence and reprint requests to Dr. Page B. Pennell, Emory Epilepsy Program, Associate Professor of Neurology, Emory University School of Medicine, 101 Woodruff Circle, Suite 6000, Atlanta, GA 30322 page.pennell{at}emoryhealthcare.org

Objective: To characterize the magnitude and course of alterations in total and free lamotrigine (LTG) clearance (Cl) during pregnancy and the postpartum period, to assess the impact of therapeutic drug monitoring (TDM) on seizure frequency, to determine the ratio to individual target LTG concentration that is associated with increased seizure risk, and to evaluate maternal postpartum toxicity.

Methods: A cohort of women were enrolled before conception or during pregnancy in this prospective, observational study. Visits occurred every 1 to 3 months with review of seizure and medication diaries, examination, and blood sampling. Total and free LTG Cls were calculated. Individualized target concentrations were used for TDM. The ratio to target concentration (RTC) was compared between patients with and without increased seizures. A receiver operating characteristic curve determined the threshold RTC that best predicts increased seizure frequency.

Results: Analysis of 305 samples in 53 pregnancies demonstrated increased total and free LTG Cl in all trimesters above nonpregnant baseline (p < 0.001), with peak increases of 94% and 89% in the third trimester. Free LTG Cl was higher in white compared with black women (p < 0.05). Increased seizure frequency (n = 36 women with epilepsy) in the second trimester was associated with a lower RTC (p < 0.001), and RTC < 0.65 was a significant predictor of seizure worsening. An empiric postpartum taper reduced the likelihood of maternal LTG toxicity (p < 0.05) (n = 27). Newborn outcomes were similar to the general population (n = 52).

Conclusions: These novel data contribute to a rational treatment plan and dosing paradigm for lamotrigine use during pregnancy, parturition, and the postpartum period.

Abbreviations: AED = antiepileptic drug; AUC = area under the curve; Cl = clearance; CV = coefficient of variation; GA = gestational age; GTCSz = generalized tonic–clonic seizure; LBW = low birth weight; LTG = lamotrigine; NICU = neonatal intensive care unit; PP = postpartum month; RTC = ratio to target concentration; SGA = small for gestational age; TDM = therapeutic drug monitoring; UGT = UDP-glucuronosyltransferase.

Supplemental data at www.neurology.org

e-Pub ahead of print on November 28, 2007, at www.neurology.org.

Supported by an NIH Specialized Center of Research (P50 MH 68036), R01 MH-71531, and an NIH grant from the National Center for Research Resources (NCRR M01-RR00039).

Disclosure: Dr. Page B. Pennell has participated in the speaker’s bureau and advisory boards for GlaxoSmithKline and UCB Pharma. She has received research support from GlaxoSmithKline, UCB Pharma, Marinus Pharmaceuticals, and the National Institutes of Health. Dr. D. Jeffrey Newport has received honoraria support from GlaxoSmithKline, Eli Lilly, Pfizer, and AstraZeneca and has received research support from the National Institutes of Health, Eli Lilly, GlaxoSmithKline, and Wyeth. Dr. James C. Ritchie has received research grant support from the National Institutes of Health, the Georgia Cancer Coalition, and the American Foundation for Suicide Prevention. Dr. Archana Koganti has participated in the speaker’s bureaus for Cyberonics and UCB Pharma and has received research support from the National Institutes of Health. Ms. Holley has received salary support for conducting research studies from the National Institutes of Health. Ms. Newman has received salary support for conducting research studies from GlaxoSmithKline, UCB Pharma, Marinus Pharmaceuticals, and the National Institutes of Health. Dr. Zachary N. Stowe has participated in the speaker’s bureaus for GlaxoSmithKline, Pfizer, and Wyeth; serves on the advisory boards for GlaxoSmithKline and Bristol Myers Squibb; and has received research grant support from Pfizer, GlaxoSmithKline, Wyeth, and the National Institutes of Health. Dr. Limin Peng has no conflicts of interest.

Received April 24, 2007. Accepted in final form August 23, 2007.






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