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

硝苯地平未能延迟早产的药物遗传学风险 (PROFOUND-PTB)

基本信息

批准号：
10173050
负责人：
Hyunyoung Jeong
金额：
$ 33.14万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-10 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10173050
关键词：
Adrenergic beta-Agonists Adverse drug effect Adverse effects Adverse event African American Alleles Animals Area Betamethasone Birth Records Blood Pressure CYP2D6 gene CYP3A4 gene CYP3A5 gene Calcium Channel Blockers Caucasians Cervical Chicago Child Clinical Clinical Data Country Data Developing Countries Dexamethasone Disease Dose Drug Kinetics Drug Prescriptions Drug Regulations Drug usage Enzymes Equilibrium Ethnic Origin Ethnic group European Face Failure Fetal Heart Rate Fetus Fibrinogen Foundations Frequencies Gene Frequency Genetic Polymorphism Goals Guidelines Heart Rate Hepatic Hepatocyte Hispanics Homozygote Hospitals Hour Human Hypotension In Vitro Incidence Individual Infant Insurance International Intramuscular Injections Knowledge Label Learning Disabilities Magnesium Sulfate Measures Mediating Medical Medicine Metabolism Minor Modeling Molecular Mothers Nifedipine Non-Steroidal Anti-Inflammatory Agents Outcome Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Pharmacotherapy Pharmacy facility Phenotype Physiological Plasma Population Postpartum Period Pregnancy Pregnant Women Premature Birth Premature Infant Premature Labor Protocols documentation Publishing Race Recommendation Regimen Research Resources Respiratory physiology Retinoids Risk Safety Smooth Muscle Solid Standardization Steroids Tachycardia Testing Therapeutic Thyroid Hormones Time Tocolysis Tocolytic Agents Translating Translations Uterine Contraction Uterus Woman Work antenatal base design dosage dose individualization drug disposition drug market drug metabolism early pregnancy ethnic difference fetal improved improved outcome interest knowledge base physically handicapped premature preterm newborn preterm premature rupture of membranes racial difference response side effect transcription factor

项目摘要

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 (DMEs) 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.

超过50%的孕妇服用一种或多种处方药，但关于安全性的数据有限，