Physiological-based Pharmacokinetics Approach to Medication Exposure During Pregnancy and Breastfeeding (PBPK)

Physiological-based Pharmacokinetics Approach to Determine the Extent of Drug Exposure of Antiseizure Medications During Pregnancy and Breastfeeding

This project focuses on anti-seizure medication (ASM) clearance and physiological factors determining blood concentrations in pregnant adult women with epilepsy and amounts of exposure to their unborn children and nursing infants.

Study Overview

• Status: Recruiting
• Conditions: Epilepsy; Pregnancy Related
• Intervention / Treatment: Drug: Lamotrigine; Drug: Levetiracetam; Drug: Oxcarbazepine

Detailed Description

The goal of this study is to develop modeling of pharmacokinetic changes for Antiseizure medications (ASMs), lamotrigine (LTG), and levetiracetam (LEV) during pregnancy and postpartum that can be used to:

1. Adjust doses in practice without obtaining frequent visits to the lab for therapeutic drug monitoring.
2. Predict exposure of ASMs in mothers and their infants in order to maintain the individualized target concentrations, thus protecting mothers from seizure worsening and minimizing fetal toxicity.

Hypotheses:

1. Drug concentrations obtained in preconception and early pregnancy predict clearance changes throughout the remainder of pregnancy for individual pregnant women with epilepsy.
2. Validated model allows the prediction of drug concentration changes at all stages throughout and after pregnancy, which will more accurately predict increased seizures and medication side effects.

Additionally, pilot data will be obtained for oxcarbazepine (OXC) in a small number of participants and contribute to data for ASMs that undergo glucuronidation (LTG).

• Study Type: Observational
• Enrollment (Estimated): 60

Contacts and Locations

• Study Contact: Name: Erica Kemp, PA; Email: kempe2@upmc.edu
• Study Contact Backup: Name: Tonge Ebai, PhD; Phone Number: 4126160730; Email: ebait@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • University of Pittsburgh
      • Contact: Tonge Ebai, PhD; Phone Number: 412-592-4018; Email: ebait@upmc.edu
      • Contact: Erica Kemp, P.A.; Email: kempe2@upmc.edu
      • Principal Investigator: Page B Pennell, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 45 years (Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Participants to be mainly recruited from Neurology and OBGYN clinics.

Description

Inclusion Criteria:

• Woman with epilepsy between the ages of 18-45 planning pregnancy or in the early first trimester of pregnancy.
• Women with epilepsy ability to maintain a daily medical diary
• Women with epilepsy ability to answer side effect questionnaires
• Women with epilepsy currently being treated with lamotrigine (LTG) or levetiracetam (LEV) or oxcarbazepine (OXC)

Exclusion Criteria:

• Women with epilepsy having history of functional seizures.
• Women with epilepsy history of other major medical illnesses including renal or hepatic disease, progressive cerebral disease,
• Women with epilepsy who have inability to maintain a seizure and medication daily diary
• Women with epilepsy with present or recent history of drug or alcohol abuse, or the use of any concomitant medications that interact with the ASM they are taking (lamotrigine, levetiracetam, oxcarbazepine).

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Lamotrigine (LTG); Participants will include women with epilepsy planning pregnancy or in the early first trimester of pregnancy and treated with lamotrigine (LTG)	Drug: Lamotrigine; Anti-seizure concentrations; Other Names: Anti-seizure medication: Lamotrigine (LTG)
Levetiracetam (LEV); Participants will include women with epilepsy planning pregnancy or in the early first trimester of pregnancy and treated with Levetiracetam (LEV)	Drug: Levetiracetam; Anti-seizure concentrations; Other Names: Anti-seizure medication: Levetiracetam (LEV)
Oxcarbazepine (OXC); Participants will include women with epilepsy planning pregnancy or in the early first trimester of pregnancy and treated with with Oxcarbazepine (OXC)	Drug: Oxcarbazepine; Anti-seizure concentrations; Other Names: Anti-seizure medication: Oxcarbazepine (OXC)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-Seizure Medication (ASM) Clearance	ASM Clearance will be calculated from measurements of lamotrigine, oxcarbazepine, and levetiracetam blood concentrations, serum creatinine and 24-hour urine collection (for levetiracetam), glucuronidated metabolite (for lamotrigine), steroid hormones, medication formulation and doses, time since recent doses, and participant weight.	Through study completion, an average of 18 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Seizure Frequency	Participants will keep a daily seizure diary throughout their participation in the study. The diary will be reviewed at each study visit.	Through study completion, an average of 18 months.
Anti-seizure Medication (ASM) Side Effects	An ASM Side Effect Questionnaire will be administered and a neurologic examination will be performed at each study visit.	Through study completion, an average of 18 months
Placental passage of Anti-Seizure Medications (ASM)	Maternal blood will be drawn and umbilical cord blood will be collected, for measurements of ASM concentrations for lamotrigine, oxcarbazepine, and levetiracetam.	Through study completion, an average of 18 months

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Page B Pennell, MD, The University of Pittsburgh

Publications and helpful links

General Publications

• Pennell PB, French JA, May RC, Gerard E, Kalayjian L, Penovich P, Gedzelman E, Cavitt J, Hwang S, Pack AM, Sam M, Miller JW, Wilson SH, Brown C, Birnbaum AK, Meador KJ; MONEAD Study Group. Changes in Seizure Frequency and Antiepileptic Therapy during Pregnancy. N Engl J Med. 2020 Dec 24;383(26):2547-2556. doi: 10.1056/NEJMoa2008663.
• Birnbaum AK, Meador KJ, Karanam A, Brown C, May RC, Gerard EE, Gedzelman ER, Penovich PE, Kalayjian LA, Cavitt J, Pack AM, Miller JW, Stowe ZN, Pennell PB; MONEAD Investigator Group. Antiepileptic Drug Exposure in Infants of Breastfeeding Mothers With Epilepsy. JAMA Neurol. 2020 Apr 1;77(4):441-450. doi: 10.1001/jamaneurol.2019.4443.
• Pennell PB, Karanam A, Meador KJ, Gerard E, Kalayjian L, Penovich P, Matthews A, McElrath TM, Birnbaum AK; MONEAD Study Group. Antiseizure Medication Concentrations During Pregnancy: Results From the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) Study. JAMA Neurol. 2022 Apr 1;79(4):370-379. doi: 10.1001/jamaneurol.2021.5487.

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2022
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: June 22, 2022
• First Submitted That Met QC Criteria: July 6, 2022
• First Posted (Actual): July 11, 2022

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: May 1, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Acids, Acyclic; Carboxylic Acids; Amides; Triazines; Pyrrolidines; Acetamides; Acetates; Dibenzazepines; Heterocyclic Compounds, 3-Ring; Pyrrolidinones; Carbamazepine; Lamotrigine; Levetiracetam; Oxcarbazepine
• Other Study ID Numbers: STUDY21090138; R01HD105305 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: We will adhere to the NIH Grants Policy Statement on Sharing of Biomedical Research Resources, including the "Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice." The results of the studies proposed here will be shared with the scientific community on a regular basis through presentations at scientific meetings and peer-reviewed publications in appropriate scientific journals. Any material resources developed as a result of this grant will be made available to other investigators once a Material Transfer Agreement has been signed between the University of Pittsburgh, University of Minnesota and the requesting investigator's institution.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No