# Pharmacogenetic Risks Operating in Failure Of Nifedipine to Delay Pre-Term Birth (PROFOUND-PTB)

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $331,426

## Abstract

Over 50% of pregnant women take one or more prescription drugs, but there are limited data on the safety,
efficacy and pharmacokinetics (PKs) of the majority of drugs used during pregnancy. Accumulating evidence
indicates that drug disposition is altered during pregnancy due to the extensive physiological changes,
including altered rate of hepatic drug metabolism. For most drugs, doses used in non-pregnant women cannot
be extrapolated to pregnancy. Yet, dosing guidelines for pregnant women have been lacking, mainly because
current understanding about altered drug disposition during pregnancy is incomplete. This subsequently leads
to an increased risk for over- or under-dosing of drugs in pregnant women and exposure of her fetus to either
adverse drug effects or maternal disease. Thorough understanding of the PK changes of drugs during
pregnancy and factors responsible for the changes is imperative to achieve optimal drug therapy during
pregnancy. The long-term goal of our research is to build a solid knowledge base for the prediction of PK
changes and the design of optimal individualized dosage regimens for pregnant women. The objectives of this
application are to provide mechanistic understanding of altered drug metabolism by cytochrome P450 (CYP)
2D6 and CYP3A4 and to translate the findings to human pregnancy. CYP2D6 and CYP3A4 are the two most
important drug-metabolizing enzymes and together responsible for metabolizing ~70% of marketed drugs.
Clinical data indicate that elimination of drugs metabolized by CYP3A4 or CYP2D6 is faster at term pregnancy
(as compared to postpartum period), but underlying mechanisms remain unclear. In previous studies, we
established models to study regulation of DME expression throughout gestation and identified factors
contributing to CYP2D6 induction during pregnancy. Specifically, our results suggest that lower hepatic retinoid
level and subsequent decreases in the expression of a transcription factor (i.e., SHP) are involved in CYP2D6
induction during pregnancy. Also, results from human hepatocytes suggest that CYP3A4-mediated drug
metabolism is highest during early pregnancy (compared to the later time points of pregnancy or postpartum
period), potentially due to changes in thyroid hormone concentration. Based on these results, we propose to:
(1) elucidate the detailed molecular mechanisms underlying CYP2D6 induction during pregnancy, and (2)
define factors responsible for temporal changes in CYP3A4-mediated drug metabolism during pregnancy. To
this end, we will perform studies ranging from in vitro/animal studies to human clinical PK studies, testing
translation of in vitro or animal findings to human pregnancy. The results are expected to have a positive
impact by laying a foundation for PK prediction of CYP2D6 or CYP3A4 substrates and guide individualized
dosing recommendations for pregnant women.

## Key facts

- **NIH application ID:** 10173050
- **Project number:** 3R01HD089455-04S1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Hyunyoung Jeong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $331,426
- **Award type:** 3
- **Project period:** 2017-08-10 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173050

## Citation

> US National Institutes of Health, RePORTER application 10173050, Pharmacogenetic Risks Operating in Failure Of Nifedipine to Delay Pre-Term Birth (PROFOUND-PTB) (3R01HD089455-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10173050. Licensed CC0.

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