Metabolome-wide association study of anti-epileptic drug treatment during pregnancy

• Type of Material: Article
• Authors: Douglas Walker, Emory University; Kayla Perry-Walker, University of Pennsylvania; Richard H. Finnell, Baylor College of Medicine; Kurt D. Pennell, Brown University; Tran Vilinh, Emory University; Ryan C. May, Emmes Corporation; Thomas F. McElrath, Harvard University; Kimford Meador, Emory University; Page B. Pennell, Harvard University; Dean Jones, Emory University
• Language: English
• Date: 2019-01-15
• Publisher: Academic Press Inc. Elsevier Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.taap.2018.12.001
• Title of Journal or Parent Work: Toxicology and Applied Pharmacology
• Volume: 363
• Start Page: 122
• End Page: 130
• Grant/Funding Information: National Institute of Mental Health (MH107205) and the National Institute of Neurological Disorders and Stroke and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NS038455, NS050659); This work was supported by funds received from the NIH Common Fund Initiative promoting collaborative activities in metabolomics research (3UO1NS038455-13S1); National Institute of Environmental Health Sciences (ES019776, ES026560, ES012870)
• Keywords: Science & Technology; Levetiracetam; Life Sciences & Biomedicine; Lamotrigine; LC-MS; Folate; High resolution metabolomics; Exposure; R Package; Plasma; Pharmacometabolomics; Pharmacology & Pharmacy; Toxicology; Outcomes; Catecholamines; Risk; Epilepsy; High-resolution mass spectrometry; Women
• Research Categories: Biology, Molecular; Health Sciences, Obstetrics and Gynecology; Biology, Neuroscience; Health Sciences, Pharmacology; Health Sciences, Toxicology

Abstract

Pregnant women with epilepsy (PWWE) require continuous anti-epileptic drug (AED) treatment to avoid risk to themselves and fetal risks secondary to maternal seizures, resulting in prolonged AED exposure to the developing embryo and fetus. The objectives of this study were to determine whether high-resolution metabolomics is able to link the metabolite profile of PWWE receiving lamotrigine or levetiracetam for seizure control to associated pharmacodynamic (PD) biological responses. Untargeted metabolomic analysis of plasma obtained from 82 PWWE was completed using high-resolution mass spectrometry. Biological alterations due to lamotrigine or levetiracetam monotherapy were determined by a metabolome-wide association study that compared patients taking either drug to those who did not require AED treatment. Metabolic changes associated with AED use were then evaluated by testing for drug-dose associated metabolic variations and pathway enrichment. AED therapy resulted in drug-associated metabolic profiles recognizable within maternal plasma. Both the parent compounds and major metabolites were detected, and each AED was correlated with other metabolic features and pathways. Changes in metabolites and metabolic pathways important to maternal health and linked to fetal neurodevelopment were detected for both drugs, including changes in one‑carbon metabolism, neurotransmitter biosynthesis and steroid metabolism. In addition, decreased levels of 5-methyltetrahydrofolate and tetrahydrofolate were detected in women taking lamotrigine, which is consistent with recent findings showing increased risk of autism spectrum disorder traits in PWWE using AED. These results represent a first step in development of pharmacometabolomic framework with potential to detect adverse AED-related metabolic changes during pregnancy.