Disparities in emergency contraceptive metabolism dictate efficacy

紧急避孕药代谢的差异决定了功效

基本信息

批准号：
10518960
负责人：
ALISON B EDELMAN
金额：
$ 79.97万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10518960
关键词：
Acetates Alleles Animal Model Animals Asthma Binding Biological Black Populations Black race Blood Blood specimen Body mass index CYP3A4 gene CYP3A5 gene Cardiovascular Diseases Cell physiology Characteristics Communicable Diseases Contraceptive Agents Contraceptive Availability Contraceptive Usage Contraceptive methods Cytochrome P450 Data Development Dose Drug Kinetics Economics Enrollment Enzymes Estradiol Failure Follicular Fluid Frequencies Gene Expression Gene Frequency Genes Genetic Genetic Predisposition to Disease Genomics Genotype Goals Half-Life Health Human Hypertension Individual Intervention Kinetics Knowledge Lead Liver Luteinizing Hormone Macaca mulatta Malignant Neoplasms Medical Metabolism Methods Modeling Monitor Obesity Oocytes Oral Other Genetics Outcome Ovarian Ovarian Follicle Ovary Ovulation Personal Satisfaction Persons Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics Phenotype Play Population Pregnancy Primates Process Progesterone Publishing Race Regression Analysis Reporting Research Risk Role Rupture Sampling Serum Sex Discrimination Site Stimulus Study Subject Testing Therapeutic Time Transvaginal Ultrasound United States Variant Woman Work aged base clinically relevant contraceptive efficacy design drug efficacy drug metabolism emergency contraception enzyme activity experience genetic variant granulosa cell health care availability health disparity health inequalities human subject inhibitor intraovarian nonhuman primate novel peer pharmacokinetics and pharmacodynamics prevent primary endpoint racial discrimination racial disparity receptor recruit reproductive response social determinants social health determinants unintended pregnancy women of color

项目摘要

SUMMARY The proposed project aims to increase our knowledge regarding the intersection of pharmacogenomics, contraceptive efficacy, and health disparities. U.S. women of color are at much greater risk of experiencing contraceptive failure, resulting in more unintended pregnancies than their white peers. While social determinants of health, such as racial discrimination and access to healthcare, contribute meaningfully to contraceptive availability and use, inherent pharmacogenomic differences could also account for significant individual-to-individual disparities in efficacy. The most effective oral emergency contraceptive (EC) method, ulipristal acetate (UPA), which works by blocking progesterone action in the preovulatory follicle, appears to be less effective in certain populations even when optimally dosed. We have demonstrated that UPA is converted to inactive metabolites by the enzyme cytochrome P450 3A5 (CYP3A5). Moreover, we established that the primate ovarian follicle, the site of UPA action as an EC, expresses remarkably high levels of CYP3A5 through the periovulatory interval and luteal development. The genotype and phenotype frequency of an active variant of CYP3A5 is significantly greater in those identifying as Black as compared to whites, with the latter possessing primarily a nonfunctional variant. Because active CYP3A5 is a major contributor to drug metabolism, we hypothesize that UPA is significantly less effective at preventing ovulation in women with the active CYP3A5 variant. In this proposal, we will determine if follicular CYP3A5 reduces intraovarian UPA levels relative to what is observed systemically (Aim 1) using the clinically relevant rhesus macaque model. Studies will also be performed to determine if blocking CYP3A5 activity leads to greater UPA efficacy in inhibiting processes essential for ovulation. In complementary human subjects studies, we plan to assess if CYP3A5 genotype (active versus inactive form) determines UPA efficacy (Aim 2). Women recruited for this study will be genotyped and categorized as possessing active or inactive CYP3A5 alleles and then assessed for UPA pharmacodynamics. We will also explore other genetic variants that might play a role in drug metabolism. The primary endpoint includes determining if significant differences exist in the rate at which UPA fails to prevent ovulation and the pharmacokinetics of UPA metabolism related to the CYP3A5 genotype. The results of the studies will determine if a genetic predisposition exists for racial disparities in contraceptive efficacy and the risk for unintended pregnancy. The broad, long-term goal of this research includes providing a means to maximize the therapeutic potential of UPA in women through testing to identify individuals at risk for failure and/or developing approaches to limit drug metabolism.

概括拟议的项目旨在增加我们对药物基因组学交叉的了解，避孕功效和健康差异。美国有色人种女性面临更大的风险避孕失败，导致比白人同龄人更多的意外怀孕。社交的同时健康的决定因素，例如种族歧视和获得医疗保健的机会，对避孕药具的可用性和使用、固有的药物基因组差异也可能是显着的原因个体与个体之间的功效差异。最有效的口服紧急避孕药（EC）方法，醋酸乌利司他 (UPA) 的作用是阻断排卵前卵泡中的黄体酮作用，似乎是即使在最佳剂量下，对某些人群的效果也较差。我们已经证明 UPA 已转换通过细胞色素 P450 3A5 (CYP3A5) 酶转化为无活性的代谢物。此外，我们确定灵长类动物卵泡是 UPA 作为 EC 发挥作用的部位，通过以下方式表达非常高水平的 CYP3A5：排卵期间隔和黄体发育。活性变体的基因型和表型频率与白人相比，黑人的 CYP3A5 含量明显更高，而后者主要拥有非功能性变体。因为活性 CYP3A5 是药物的主要贡献者新陈代谢，我们假设 UPA 在预防患有以下疾病的女性排卵方面的效果明显较差活性 CYP3A5 变体。在本提案中，我们将确定卵泡 CYP3A5 是否会降低卵巢内 UPA 水平相对于使用临床相关恒河猴模型系统观察到的情况（目标 1）。研究还将进行以确定阻断 CYP3A5 活性是否会导致 UPA 抑制效果更大排卵所必需的过程。在补充人类受试者研究中，我们计划评估 CYP3A5 是否基因型（活性形式与非活性形式）决定 UPA 功效（目标 2）。为这项研究招募的女性将进行基因分型并分类为具有活性或非活性 CYP3A5 等位基因，然后评估 UPA 药效学。我们还将探索可能在药物代谢中发挥作用的其他遗传变异。这主要终点包括确定 UPA 未能预防的发生率是否存在显着差异排卵和与 CYP3A5 基因型相关的 UPA 代谢的药代动力学。结果研究将确定是否存在遗传倾向导致避孕效果和避孕效果方面的种族差异意外怀孕的风险。这项研究的广泛、长期目标包括提供一种方法通过测试识别有失败风险的个体，最大限度地发挥 UPA 对女性的治疗潜力和/或开发限制药物代谢的方法。