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CAMCAP: Cholesterol and CYP3A4/5 Metabolism Across Pregnancy and Postpartum

Sponsor
Northwestern University (Other)
Overall Status
Enrolling by invitation
CT.gov ID
NCT05504889
Collaborator
Purdue University (Other)
210
Enrollment
1
Location
24
Anticipated Duration (Months)
8.7
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study addresses the second aim of the grant (R01 HD0899455), which is to determine temporal changes in CYP3A4-mediated drug metabolism sequentially across pregnancy and after birth.

Condition or Disease Intervention/Treatment Phase

    Detailed Description

    This study addresses the second aim of the grant (R01 HD0899455), which is to determine temporal changes in CYP3A4-mediated drug metabolism sequentially across pregnancy and after birth.

    In studies with human hepatocytes, we found that serum from women in the first trimester led to the highest CYP3A4 expression compared to those from the second or third trimester or after birth. Among the hormones with elevated plasma concentrations in early pregnancy, our studies revealed that thyroid hormone enhances CYP3A4 expression in human hepatocytes. Based on the results, we hypothesized that CYP3A4-mediated drug metabolism is highest during early pregnancy (compared to the later time points of pregnancy or postpartum period) in part due to changes in thyroid hormone concentration.

    To test this hypothesis, we will evaluate the conversion of endogenous cholesterol to its 4β-hydroxycholesterol metabolite, which is facilitated by CYP3A4. To assess additional factors that affect CYP3A activity, we will obtain DNA. About 75% of African Americans, but only 10-20% of people of European descent, carry the active allele CYP3A5*1, which significantly increases the clearance of many CYP3A4/5 substrates, including the conversion of cholesterol to 4β-hydroxycholesterol.

    Study Design

    Study Type:
    Observational
    Anticipated Enrollment :
    210 participants
    Observational Model:
    Cohort
    Time Perspective:
    Prospective
    Official Title:
    Cholesterol and CYP3A4/5 Metabolism Across Pregnancy and Postpartum
    Actual Study Start Date :
    Jun 17, 2022
    Anticipated Primary Completion Date :
    Dec 31, 2023
    Anticipated Study Completion Date :
    Jun 17, 2024

    Arms and Interventions

    Arm Intervention/Treatment
    OPTIMOM residual samples

    Residual plasma samples collected in one of our prior studies monthly across pregnancy (OPTIMOM, NICHD 1U54HD085601-01, Clinical Trials.gov ID NCT02519790; K. Wisner, PI) will be evaluated for cholesterol and 4β-hydroxycholesterol. These samples were obtained from women who gave their consent for use of their blood samples for future studies. All OPTI-MOM participants have been genotyped for variants in CYP3A5 using commercial allelic discrimination assays (ThermoFisher Scientific, Waltham, MA, with Taqman probes.)
    Newly recruited subjects

    Plasma samples will be collected from newly recruited subjects.

    Outcome Measures

    Primary Outcome Measures

    1. Change in the endogenous metabolic ratio of 4β-hydroxycholesterol to cholesterol (4β-OHC/C, a marker of CYP3A activity) from early pregnancy through 17 weeks 6 days after delivery [Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum]

      plasma concentrations

    Secondary Outcome Measures

    1. Impact of active CYP3A5 phenotype on the 4β-hydroxycholesterol to cholesterol metabolic ratio [Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum]

      plasma concentrations

    2. Impact of estradiol concentrations on ratio in the early first trimester of pregnancy [Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum]

      plasma concentrations

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 45 Years
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:

    • English speaking

    • Pregnant before 14w0d OR postpartum between before 18w0d

    • Singleton gestation (as this will result in more consistent inter-individual measures)

    Exclusion Criteria:

    • Chronic use of compounds that are substrates or inhibitors of CYP3A4 inhibitors, which will interfere with the concentrations and ratio. Potent inhibitors include clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal and grapefruit. Inducers of CYP3A4 include phenobarbital, phenytoin, rifampicin, St. John's Wort and glucocorticoids.

    • Diagnosis of alcoholism or substance use.

    • Covid infection or within 4 weeks of positive test due to possible effect on hepatic function

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Northwestern University Asher Center for the Study and Treatment of Depressive Disorders Chicago Illinois United States 60611

    Sponsors and Collaborators

    • Northwestern University
    • Purdue University

    Investigators

    • Principal Investigator: Katherine L Wisner, M.D., M.S., Northwestern University
    • Principal Investigator: Hyunyoung Jeong, PharmD, PhD, Purdue University
    • Principal Investigator: Catherine S Stika, M.D., Northwestern University

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Katherine Wisner, Professor, Northwestern University
    ClinicalTrials.gov Identifier:
    NCT05504889
    Other Study ID Numbers:
    • STU00217170
    First Posted:
    Aug 17, 2022
    Last Update Posted:
    Aug 17, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Katherine Wisner, Professor, Northwestern University
    pregnancy
    CYP3A
    postpartum
    hydroxycholesterol ratio

    Study Results

    No Results Posted as of Aug 17, 2022