title: MODEL-BASED LAMOTRIGINE CLEARANCE CHANGES DURING PREGNANCY: CLINICAL IMPLICATION.
abstract: OBJECTIVE
  The objective of the study was to characterize changes in the oral clearance (CL/F) of lamotrigine (LTG) over the course of pregnancy and the postpartum period through a model-based approach incorporating clinical characteristics that may influence CL/F, in support of developing clinical management guidelines.
  
  
  METHODS
  Women receiving LTG therapy who were pregnant or planning pregnancy were enrolled. Maternal blood samples were collected at each visit. A pharmacokinetic analysis was performed using a population-based, nonlinear, mixed-effects model.
  
  
  RESULTS
  A total of 600 LTG concentrations from 60 women (64 pregnancies) were included. The baseline LTG CL/F was 2.16 L/h with a between-subject variability of 40.6%. The influence of pregnancy on CL/F was described by gestational week. Two subpopulations of women emerged based on the rate of increase of LTG CL/F during pregnancy. The gestational age-associated increase in CL/F displayed a ten-fold higher rate in 77% of the women (0.118 L/h/week) compared to 23% (0.0115 L/h/week). The between-subject variability in these slopes was 43.0%. The increased CL/F at delivery declined to baseline values with a half-life of 0.55 weeks.
  
  
  CONCLUSIONS
  The majority of women had a substantial increase in CL/F from 2.16 to 6.88 L/h by the end of pregnancy, whereas 23% of women had a minimal increase. An increase in CL/F may correspond to decreases in LTG blood concentrations necessitating the need for more frequent dosage adjustments and closer monitoring in some pregnant women with epilepsy. Postpartum doses should be tapered to preconception dose ranges within 3 weeks of delivery.
authors.affiliation: Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Akshanth R
authors.initials: AR
authors.lastname: Polepally
authors.affiliation: Department of Neurology and Division of Women's Health at Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Page B
authors.initials: PB
authors.lastname: Pennell
authors.affiliation: Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Brundage
authors.affiliation: Department of Psychiatry, Pediatrics, and Obstetrics & Gynecology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Zachary N
authors.initials: ZN
authors.lastname: Stowe
authors.affiliation: Departments of Psychiatry and Obstetrics & Gynecology, The Ohio State University College of Medicine, Columbus, Ohio ; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: D Jeffrey
authors.initials: DJ
authors.lastname: Newport
authors.affiliation: Department of Psychiatry, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Adele C
authors.initials: AC
authors.lastname: Viguera
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia ; Department of Pathology, Emory University School of Medicine.
authors.forename: James C
authors.initials: JC
authors.lastname: Ritchie
authors.affiliation: Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Birnbaum