Physiological-based Pharmacokinetics Approach to Determine the Extent of Drug Exposure of Antiseizure Medications During Pregnancy and Breastfeeding
Conditions: Epilepsy, Pregnancy Related
Sponsor: University of Pittsburgh

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This project focuses on anti-seizure medication (ASM) clearance and physiological factors in pregnant 
women with epilepsy. Recruitment will occur in the greater Pittsburgh, Pennsylvania area; we will recruit 
minorities in accordance with their representation in the region. 
 
1. 
Risks to Human Participants. 
Involvement of participants: The protocol for this grant will be developed with full consideration of the 
ethical standards of the PITT IRB. The PITT IRB oversees research protocols at UPMC, Magee 
Womens Hospital and other affiliated hospitals. Participants will be presented with the informed consent by 
the UPMC study staff (site principal investigator, co-investigator, research advanced practice provider (APP) 
or research coordinator), allowed to read over it, and then any questions they have concerning the project 
will be addressed. Each participant will receive a copy of their signed informed consent, and an 
additional copy will be filed in their medical records. Participants will include women with epilepsy 
planning pregnancy within the next 6 months and treated with lamotrigine (LTG) or levetiracetam (LEV) 
by their clinical neurologist. This is a prospective, observational study and the ASM regimens will 
not be chosen or changed for the purpose of this study. 
 
Sources of research data will be obtained from the participants’ medical records and interview, 
physical examination, seizure and medication diaries, questionnaires, blood, and urine assays. 
Details of the data collection are given below. 
 
Participant population: A total of 60 participants (in order to enroll 30 per ASM group) between the ages 
of 14-45 years old will be recruited for this study. Only women will be recruited given the specific aims 
of the study. 
 
Participants will be primarily recruited from UPMC neurology and obstetrics clinics by use of flyers in the 
waiting areas and exam rooms and weekly review of upcoming appointments by the study staff. The 
participant can receive and continue their care at another medical institution and participate in this 
observational study at UPMC. 
 
Participants will be excluded if they have history of psychogenic non-epileptic spells, other major 
medical illness including renal or hepatic disease, progressive cerebral disease, inability to maintain a 
seizure and medication daily diary, present or recent history of drug or alcohol abuse, polytherapy with 
other interacting ASMs, or the use of any concomitant medications that interact with the ASM they are 
Protocol Title 
Physiological-based Pharmacokinetics Approach to 
Determine the Extent of Drug Exposure of Antiseizure 
Medications During Pregnancy and Breastfeeding  
Principal 
Investigator/Faculty 
Advisor 
Name: Page Pennell 
Department: Neurology 
Telephone Number: 412-692-4622 
Email Address: pap117@pitt.edu 
Study Coordinator 
Name: Kerry Oddis 
Department: Neurology 
Telephone Number: 412-692-4918 
Institutional Email Address: kmo18@pitt.edu 
Version 
Number/Date: 
Version2/25/2022 
 

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taking (lamotrigine or levetiracetam). 
 
Study Procedures: Schedule of Events for Cohort Participants 
Study Visit 
01 
02 
03 
04 
05 
06 
Study Visit Timing 
Precon- 
ception 
1st TM 
2nd TM 
3rd TM 
Birth 
6-12 wks 
postpartum 
Clinical Evaluations 
Eligibility Checklist, Contact information 
X 
Informed Consent 
X 
Demographics 
X 
Socioeconomic Status 
X 
Family History 
X 
Preconception OB/Gyn History 
X 
Initial Physical & Neurological Exam, Vital 
Signs 
X 
Brief neurologic exam, Vital Signs 
X 
X 
X 
X 
X 
Medical History with updates 
X 
X 
X 
X 
X 
X 
Seizure Factors (Classification of Seizures, 
Etiology, and Syndromes by Age of Onset, and 
Seizure Update) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
ASM Dosing regimen with dates of changes 
X 
X 
X 
X 
X 
X 
Non-ASM Medications and Vitamins 
X 
X 
X 
X 
X 
X 
Paper Questionnaires 
 
 
 
 
 
 
ASM Side Effect Questionnaire 
X 
X 
X 
X 
X 
X 
Paper Diary 
 
 
 
 
 
 
Seizure and Medication Calendar Reviews 
X 
X 
X 
X 
X 
X 
Medical Record Review 
 
 
 
 
 
 
Ultrasound results 
 
X 
 
 
 
 
OB & Neonatal Outcomes 
 
 
 
 
X 
 
Medical Record Labs for OB care 
 
 
X 
 
 
 
Local ASM Levels 
X 
X 
X 
X 
X 
X 
Ancillary Studies (EEG/MRI/CT) 
X 
 
 
 
 
 
Laboratory Evaluations * 
 
 
 
 
 
 
ASM concentrations  
X 
X 
X 
X 
X 
X 
Hormones 
X 
X 
X 
X 
X 
X 
Genetic sampling 
X 
 
 
 
 
 
Serum Creatine for LEV participants 
X 
X 
X 
X 
X 
X 
24-hour Urine collection for LEV participants 
 
X 
X 
X 
X 
 
LTG 2-N-GLU for LTG participants 
X 
X 
X 
X 
X 
X 
Cord Blood, placental sample at Birth 
 
 
 
 
X 
 
Volume 
39 ml 
30ml 
30ml 
30ml 
30ml 
30ml 
 
TM = trimester 
*Microsamples will be obtained in the participants’ homes every two weeks after a positive pregnancy test x 3, and every 
week after delivery x 3. The participants will be instructed to fill out the  Side Effects Questionnaire on the same day as the 
postpartum microsamples samples, with adjustment in the survey to query about symptoms over the past week (instead of the 
past four weeks).  
 
 

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Data and/or Specimen Collection and Analysis: 
Samples will be collected at the Kaufmann Medical Building and Magee Women’s Hospital. 
i. 
Data collected: 
a. 
ASM Side Effects Questionnaire 
b. 
Seizure and medication daily diary 
c. 
Biological samples: blood, urine, breast milk, umbilical cord blood 
d. 
Demographic data 
e. 
Pharmacy-related data 
f. 
Seizure and outcome data 
g. 
Biological samples will be analyzed in the Birnbaum Lab, Fairview Research Laboratory 
(Minnesota), or Presbyterian Lab (Pennsylvania). 
h. 
Blood samples from mother 
i. ASM concentrations 
ii. LTG 2-N-GLU for LTG participants 
iii. Hormones (including estradiol and progesterone concentrations) 
iv. Serum and urine creatinine 
v. DNA 
i. 
Blood samples from infants (umbilical cord and heel stick/micro sampling): 
i. ASM concentrations 
ii. LTG 2-N-GLU for LTG participants 
iii. DNA 
 
Potential Risks: 
i. 
Potential risks include pain and rare instances of localized bleeding, bruising, infection 
and/or fainting from the needle sticks required to obtain blood samples from the 
participant. The umbilical cord sample will be obtained after the cord is severed and will 
not pose any discomfort or danger to the participants or the newborn. 
 
ii. 
Data and records collected on participants in connection with this research project 
will be  held confidential unless specifically required to be disclosed by state or 
federal law. Their records will become part of their hospital charts and study file 
books. They will not be personally identified in any publication that may come from 
this project. 
 
2. 
Adequacy of Protection Against Risks. 
Informed Consent and Assent: Eligibility for volunteer participants will be reviewed by the research 
study Advanced Practice Provider (APP) and research coordinator. All persons interested in the study 
will be contacted by the study APP who will describe the details of the study, ensure that the 
prospective participant meets all inclusion/exclusion criteria and, if so, will ask them to participate. 
Persons verbally agreeing to participate will be mailed consent forms containing the details of the 
study. This will provide the individual with the time and privacy to make a decision on whether or not to 
participate in the study. Follow-up telephone calls will be made within two weeks to ensure that the 
potential participant has received the consent forms and to address any questions about the study. No 
study related procedures will take place until a consent form is signed. Participants will be informed that 
they can withdraw at any time during the study without any consequences. The original signed consent 
forms will be kept on file by the research coordinator/APP. 
 
Vulnerable Participants: While the project is specific to pregnant women and includes minors, the 
project does not result in deviation from the participants’ standard of care throughout the study. The 
study will be carefully described to the participants prior to their consent. Any benefits as a result of 
the research data will be used to manage/improve health care in this exact population (pregnant 14- 

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45 year old females with epilepsy). 
 
Confidentiality: To ensure confidentiality, all participants enrolled in the study will be assigned a 
study identification code. This code will be used on all study related data collection forms except for 
those on which the use of personal identifiers is mandatory (e.g., informed consent form). Forms 
that link the name of the participant and the participant identification code will be kept in a locked 
cabinet inside a locked office under the supervision of Dr. Pennell and in an electronic file stored on 
a password protected, strongly encrypted computer server that meets HIPAA guidelines. Access to 
participants’ identifiable information will be limited to those that require this information such as the 
principal and co- investigators or others who have direct contact with study participants, such as the 
study nurses and coordinators. Any personnel with data access will be identified and listed on the 
HIPAA form. 
 
3. Potential Benefits of the Proposed Research to Research Participants and Others 
i. 
The potential risks to the participant are balanced by the potential benefit of gaining 
understanding of how to optimize dosing of LTG and LEV during pregnancy and postpartum. 
Knowledge gained may be applicable to any future pregnancies of these participants. 
ii. Compensation is not considered a benefit for this study as it is based on the amount of time 
spent rather than risk. Participants will be paid a total of $625 for participation in the entire 
study protocol for their travel costs, time and inconvenience ($75 for enrollment and birth 
visits, $50 for each trimester visit and the 6-12 weeks postpartum visit, $25 per 
microsample obtained x6), $75 for breast milk collection, and $50 for infant heel stick. If the 
participant completes only some of the study visits and/or microsamples, then she will be 
reimbursed accordingly. Parking will be covered by tokens provided by the study staff. 
iii. Participants are informed that they can discontinue participation in the study at any time 
and still be paid for the time they put in. 
 
4. Importance of Knowledge to be Gained 
Our long-term goal is to prospectively determine individualized dosing adjustments during pregnancy 
to maintain therapeutic concentrations for LTG and LEV, as well as drugs that undergo the same 
mechanisms of elimination. In addition, this research will provide a framework that can be extended to 
investigations of other ASMs and additional drug classes.