The impact of pregnancy on the pharmacokinetics of antiseizure medications: A systematic review and meta-analysis of data from 674 pregnancies

Georgios Schoretsanitis; Kristina M Deligiannidis; Nicholas Kasperk; Chiara Theresa Schmidt; Sarah Kittel-Schneider; Peter Ter Horst; Maya Berlin; Elkana Kohn; Eline M P Poels; Deepti Zutshi; Torbjörn Tomson; Olav Spigset; Michael Paulzen

doi:10.1016/j.pnpbp.2024.111030

The impact of pregnancy on the pharmacokinetics of antiseizure medications: A systematic review and meta-analysis of data from 674 pregnancies

Prog Neuropsychopharmacol Biol Psychiatry. 2024 May 16:133:111030. doi: 10.1016/j.pnpbp.2024.111030. Online ahead of print.

Affiliations

¹ Department of Psychiatry, Psychotherapy and Psychosomatics, Hospital of Psychiatry, University of Zurich, Zurich, Switzerland; The Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA; Department of Psychiatry at the Donald and Barbara Zucker School of Medicine at Northwell/Hofstra, Hempstead, NY, USA. Electronic address: george.schor@gmail.com.
² The Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA; The Departments of Obstetrics & Gynecology and Molecular Medicine at the Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA; Department of Psychiatry at the Donald and Barbara Zucker School of Medicine at Northwell/Hofstra, Hempstead, NY, USA. Electronic address: kdeligian1@northwell.edu.
³ Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, and JARA - Translational Brain Medicine, Aachen, Germany. Electronic address: n.kasperk@yahoo.de.
⁴ Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, and JARA - Translational Brain Medicine, Aachen, Germany. Electronic address: chiara.theresa.schmidt@rwth-aachen.de.
⁵ Department of Psychiatry and Neurobehavioural Science, University College Cork, Acute Mental Health Unit, Cork University Hospital, Wilton, Cork, Ireland. Electronic address: SKittelSchneider@ucc.ie.
⁶ Department of Clinical Pharmacy, Isala Medical Centre, Dokter van Heesweg 2, 8025 AB Zwolle, the Netherlands. Electronic address: p.g.j.ter.horst@isala.nl.
⁷ Clinical Pharmacology and Toxicology Unit, Shamir (Assaf Harofeh) Medical Center, Faculty of Medical and Health Sciences, Tel-Aviv University, Tel-Aviv, Israel. Electronic address: MayaB@shamir.gov.il.
⁸ Clinical Pharmacology and Toxicology Unit, Shamir (Assaf Harofeh) Medical Center, Faculty of Medical and Health Sciences, Tel-Aviv University, Tel-Aviv, Israel. Electronic address: elkanak@shamir.gov.il.
⁹ Department of Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address: e.poels@erasmusmc.nl.
¹⁰ Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: dzutshi@med.wayne.edu.
¹¹ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: torbjorn.tomson@regionstockholm.se.
¹² Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: olav.spigset@legemidler.no.
¹³ Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, and JARA - Translational Brain Medicine, Aachen, Germany; Alexianer Hospital Aachen, Aachen, Germany. Electronic address: M.Paulzen@alexianer.de.

PMID: 38762161
DOI: 10.1016/j.pnpbp.2024.111030

Abstract

Objective: Increasing evidence suggests that the physiological changes of pregnancy may impact pharmacokinetics of antiseizure medications (ASM), and this may affect treatment outcomes. The aim of this study was to quantify the pregnancy impact on the ASM pharmacokinetics.

Methods: A systematic literature search was conducted in PubMed/EMBASE in November 2022 and updated in August 2023 for studies comparing levels of ASM in the same individuals during pregnancy and in the preconception/postpartum period. Alteration ratios between the 3rd trimester and baseline were estimated. We also performed a random-effects meta-analysis calculating between-timepoint differences in mean differences (MDs) and 95% confidence intervals (95%CIs) for dose-adjusted plasma concentrations (C/D ratios). Study quality was assessed using the ClinPK guidelines.

Results: A total of 65 studies investigating 15 ASMs in 674 pregnancies were included. The largest differences were reported for lamotrigine, oxcarbazepine and levetiracetam (alteration ratio 0.42, range 0.07-2.45, 0.42, range 0.08-0.82 and 0.52, range 0.04-2.77 respectively): accordingly, C/D levels were lower in the 3rd trimester for lamotrigine, levetiracetam and the main oxcarbazepine metabolite monohydroxycarbazepine (MD = -12.33 × 10^-3, 95%CI = -16.08 to -8.58 × 10^-3 (μg/mL)/(mg/day), p < 0.001, MD = -7.16 (μg/mL)/(mg/day), 95%CI = -9.96 to -4.36, p < 0.001, and MD = -4.87 (μg/mL)/(mg/day), 95%CI = -9.39 to -0.35, p = 0.035, respectively), but not for oxcarbazepine (MD = 1.16 × 10^-3 (μg/mL)/(mg/day), 95%CI = -2.55 to 0.24 × 10^-3, p = 0.10). The quality of studies was acceptable with an average rating score of 11.5.

Conclusions: Data for lamotrigine, oxcarbazepine (and monohydroxycarbazepine) and levetiracetam demonstrate major changes in pharmacokinetics during pregnancy, suggesting the importance of therapeutic drug monitoring to assist clinicians in optimizing treatment outcomes.

Keywords: Antiseizure medications; Lamotrigine; Levetiracetam; Pharmacokinetics; Pregnancy; Therapeutic drug monitoring; Women's mental health.

Publication types

Review