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，但安全性数据有限，妊娠期间使用的大多数药物的功效和药代动力学（PK）。积累证据表明药物分布在怀孕期间由于广泛的生理变化而改变，包括肝脏药物代谢率的改变。对于大多数药物，非孕妇使用的剂量不能可以推断为怀孕。然而，缺乏针对孕妇的剂量指南，主要是因为目前对妊娠期间药物处置改变的理解并不完整。这随后导致孕妇服用药物过量或不足以及胎儿接触其中任何一种药物的风险增加药物不良反应或母体疾病。深入了解药物在用药过程中的PK变化怀孕和导致变化的因素对于在怀孕期间实现最佳药物治疗至关重要怀孕。我们研究的长期目标是为 PK 预测建立坚实的知识库孕妇最佳个体化剂量方案的变化和设计。本次活动的目标应用旨在提供对细胞色素 P450 (CYP) 改变药物代谢的机制理解 2D6 和 CYP3A4 并将这些发现转化为人类妊娠。 CYP2D6 和 CYP3A4 是两个最重要的药物代谢酶 (DME)，共同负责代谢约 70% 的市售药物药物。临床数据表明，足月时 CYP3A4 或 CYP2D6 代谢的药物消除速度更快怀孕期间（与产后期相比），但潜在机制仍不清楚。在之前的研究中，我们建立了模型来研究整个妊娠期间 DME 表达的调节，并确定妊娠期间 CYP2D6 诱导的影响因素。具体来说，我们的结果表明，肝功能降低类维生素A水平和随后转录因子（即SHP）表达的减少参与妊娠期间 CYP2D6 诱导。此外，人肝细胞的结果表明 CYP3A4 介导的药物代谢在怀孕早期最高（与怀孕后期或产后期），可能是由于甲状腺激素浓度的变化。根据这些结果，我们提议：（1）阐明妊娠期间 CYP2D6 诱导的详细分子机制， (2) 定义导致 CYP3A4 介导的药物代谢时间变化的因素怀孕。为此，我们将进行从体外/动物研究到人体临床 PK 的研究研究，测试体外或动物研究结果对人类怀孕的转化。预计结果将有为CYP2D6或CYP3A4底物的PK预测奠定基础并指导产生积极影响针对孕妇的个体化剂量建议。