Clinical trial NCT05504889: Cholesterol and CYP3A4/5 Metabolism Across Pregnancy and Postpartum
Official title: Cholesterol and CYP3A4/5 Metabolism Across Pregnancy and Postpartum
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pregnancy Related
Keywords: pregnancy
CYP3A
postpartum
hydroxycholesterol ratio
Lead sponsor: Northwestern University
Sponsor class: OTHER
Collaborators: name: Purdue University
First posted: 2022-08-17
Enrollment: 36
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Community sample of pregnant or postpartum woman in areas surrounding Chicago, IL.

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum
Secondary outcomes:
measure: Impact of active CYP3A5 phenotype on the 4β-hydroxycholesterol to cholesterol metabolic ratio
timeFrame: Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum
measure: Impact of estradiol concentrations on ratio in the early first trimester of pregnancy
timeFrame: Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University Asher Center for the Study and Treatment of Depressive Disorders
state: Illinois
Study officials:
affiliation: Northwestern University
name: Katherine L Wisner, M.D., M.S.
role: PRINCIPAL_INVESTIGATOR
affiliation: Purdue University
name: Hyunyoung Jeong, PharmD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Northwestern University
name: Catherine S Stika, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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citation: 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.
citation: 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.
citation: 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.
citation: 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.