Cholesterol and CYP3A4/5 Metabolism Across Pregnancy and Postpartum

NCT05504889 | Completed

• 1 other identifier: STU00217170
• Study Type: observational
• Target: 36
• Locations: 1 country
• Sites: 1

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.

Conditions

Pregnancy Related

Keywords

pregnancy; CYP3A; postpartum; hydroxycholesterol ratio

Outcome Measures

Primary Outcomes (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

  plasma concentrations

  Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum

Secondary Outcomes (2)

• Impact of active CYP3A5 phenotype on the 4β-hydroxycholesterol to cholesterol metabolic ratio

  Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum

• Impact of estradiol concentrations on ratio in the early first trimester of pregnancy

  Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum

Study Arms (2)

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.

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Community sample of pregnant or postpartum woman in areas surrounding Chicago, IL.

You may qualify if:

• English speaking
• Pregnant before 14w0d OR postpartum between before 18w0d
• Singleton gestation (as this will result in more consistent inter-individual measures)

You may not qualify if:

• 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

Sponsors & Collaborators

• Northwestern University: lead
• Purdue University: collaborator

Study Sites (1)

Northwestern University Asher Center for the Study and Treatment of Depressive Disorders

Chicago, Illinois, 60611, United States

Location

Related Publications (7)

• Bjorkhem-Bergman L, Backstrom T, Nylen H, Ronquist-Nii Y, Bredberg E, Andersson TB, Bertilsson L, Diczfalusy U. Comparison of endogenous 4beta-hydroxycholesterol with midazolam as markers for CYP3A4 induction by rifampicin. Drug Metab Dispos. 2013 Aug;41(8):1488-93. doi: 10.1124/dmd.113.052316. Epub 2013 May 14.

  PMID: 23674608 BACKGROUND

• Tomalik-Scharte D, Lutjohann D, Doroshyenko O, Frank D, Jetter A, Fuhr U. Plasma 4beta-hydroxycholesterol: an endogenous CYP3A metric? Clin Pharmacol Ther. 2009 Aug;86(2):147-53. doi: 10.1038/clpt.2009.72. Epub 2009 May 20.

  PMID: 19458613 BACKGROUND

• Bergstrom H, Helde Frankling M, Klasson C, Lovgren Sandblom A, Diczfalusy U, Bjorkhem-Bergman L. CYP3A Activity in End-of-Life Cancer Patients Measured by 4beta-Hydroxycholesterol/cholesterol Ratio, in Men and Women. Cancers (Basel). 2021 Sep 18;13(18):4689. doi: 10.3390/cancers13184689.

  PMID: 34572915 BACKGROUND

• Penzak SR, Rojas-Fernandez C. 4beta-Hydroxycholesterol as an Endogenous Biomarker for CYP3A Activity: Literature Review and Critical Evaluation. J Clin Pharmacol. 2019 May;59(5):611-624. doi: 10.1002/jcph.1391. Epub 2019 Feb 12.

  PMID: 30748026 BACKGROUND

• Nylen H, Sergel S, Forsberg L, Lindemalm S, Bertilsson L, Wide K, Diczfalusy U. Cytochrome P450 3A activity in mothers and their neonates as determined by plasma 4beta-hydroxycholesterol. Eur J Clin Pharmacol. 2011 Jul;67(7):715-22. doi: 10.1007/s00228-010-0984-1. Epub 2011 Jan 19.

  PMID: 21246351 BACKGROUND

• Naito T, Kubono N, Ishida T, Deguchi S, Sugihara M, Itoh H, Kanayama N, Kawakami J. CYP3A activity based on plasma 4beta-hydroxycholesterol during the early postpartum period has an effect on the plasma disposition of amlodipine. Drug Metab Pharmacokinet. 2015 Dec;30(6):419-24. doi: 10.1016/j.dmpk.2015.08.008. Epub 2015 Sep 3.

  PMID: 26654672 BACKGROUND

• Kim AH, Kim B, Rhee SJ, Lee Y, Park JS, Lee SM, Kim SM, Lee S, Yu KS, Jang IJ, Cho JY. Assessment of induced CYP3A activity in pregnant women using 4beta-hydroxycholesterol: Cholesterol ratio as an appropriate metabolic marker. Drug Metab Pharmacokinet. 2018 Jun;33(3):173-178. doi: 10.1016/j.dmpk.2018.04.004. Epub 2018 Apr 25.

  PMID: 29759884 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

endogenous cholesterol, 4-beta-hydroxycholesterol, estradiol

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 15, 2022
• First Posted: August 17, 2022
• Study Start: June 17, 2022
• Primary Completion: June 30, 2023
• Study Completion: June 30, 2023
• Last Updated: April 24, 2024

Record last verified: 2024-04

Locations

US (1)