Pharmacokinetic Characterization Of Antiseizure Medications At Different Stages Of Life In Women With Epilepsy

Abstract

Antiseizure medications (ASMs) are prescribed for chronic conditions like epilepsy. Physiological and hormonal changes over an individual's lifespan can decrease ASM concentrations, impacting seizure frequency and clinical outcomes. This thesis examines pharmacokinetics in underrepresented groups of women with epilepsy during pregnancy, postpartum, and postmenopause. Trends in pregnancy and lactation related post-marketing commitments (PMCs) and post-marketing requirements (PMRs) for new molecular entities approved by the Food and Drug Administration between 2000-2022 were characterized. A steady increase in PMRs/PMCs was observed following enactment of Food and Drug Administration Amendments Act and Pregnancy and Lactation Labeling Rule. My primary project utilized data from the Maternal Outcomes & Neurodevelopmental Effects of Anti-epileptic Drugs (MONEAD) study, an NIH-funded observational study spanning 20 centers and encompassing pregnant women with epilepsy (PWWE) and non-pregnant women with epilepsy (NPWWE). It centered on modeling Levetiracetam (LEV) apparent clearance (CL/F) via a population pharmacokinetic approach, predicting a 15% higher typical volume of distribution in pregnant state. Throughout pregnancy, CL/F of PWWE increased by 24.1%, 43.1%, and 58.9% by trimesters 1, 2, and 3, respectively, compared to postpartum. Covariates such as weight, gestational age, and weeks postpartum explained variability in pharmacokinetic parameters. Maternal and umbilical cord plasma concentrations of ASMs at delivery were assessed. The umbilical cord to maternal plasma concentration ratios were close to 1.0, indicating placental passage of ASMs. Significant correlations were noted between maternal and umbilical plasma concentrations for most ASMs. My second project analyzed real-world data from individuals taking lamotrigine (LTG) for epilepsy. We aimed to understand age and sex-related variability in LTG prescription and clearance, focusing on postmenopausal women. LTG prescription in postmenopausal women was less frequent than in younger women but more frequent than in older men. Postmenopausal women showed a 22% lower LTG CL/F compared to younger women and a 9% lower CL/F compared to older men. Co-administration of an inducer and smoking increased LTG CL/F by 49% and 11%, respectively, while an inhibitor decreased CL/F by 51%. The results of this thesis add robust evidence to inform clinical management of LEV therapy in PWWE and LTG in postmenopausal women with epilepsy.