Comprehensive evaluation of the safety and utility of pravastatin in prevention of preeclampsia in high-risk pregnant women

摘要-临床项目 子痫前期(PE)影响3%至8%的孕妇，仍然是发病率和 死亡率。在没有有效的PE治疗的情况下，预防产妇发病率的唯一方法就是分娩。由于 PE和心血管疾病的相似之处，我们和其他人已经证明了 普伐他汀(PRA)逆转PE的几个病理生理途径和表型特征。贴上标签 将PRA列为X类的主要原因是没有关于其在怀孕中的使用的迹象，作为数据 来自实验动物模型和妊娠早期暴露于PRA的孕妇的队列没有 支持X类药物的致畸性声明。最近，作为NICHD-OPRU网络中的一个站点 在从FDA获得IND后，我们完成了一项试点、双盲、随机临床试验(RCT)。 对于PE高危孕妇，随机给予10毫克PRA或安慰剂。这项研究显示出有利于 PRA在该人群中的母婴安全性和药代动力学(PK)谱。已完成的试点试验 使用了IND中允许的最低剂量的PRA(10毫克)，以及我们在此应用中建议的研究 将以FDA Ind已经批准的较高剂量(20毫克)评估PRA。 我们的假设是，当普伐他汀用于PE高危孕妇时，表现出良好的疗效 母婴安全性、药效学(PD)和PK配置文件。我们提出了一种双盲安慰剂- 对照研究100-120例PE高危孕妇随机对照试验 确定孕期PRA的母儿安全状况；(2)确定是否早期预防 高危女性的PRA治疗逆转了与PE相关的血管生成失衡，(3)确定 孕期PRA的PK及其代谢产物的形成(与产后相比)，以及 (4)确定SNPs在编码摄取和外排转运蛋白和磺基转移酶基因中的作用 酵素对母亲暴露于PRA的影响。 安全性、PK参数和PD的数据将在不同剂量之间进行比较 确定哪种剂量可产生最显著的局部放电效应和最有利的安全性。这 确定将为实施更大的临床试验提供所需的框架，以确定 PRA预防PE的能力。

ABSTRACT—Clinical Project Preeclampsia (PE) affects 3% to 8% of pregnant women and remains a major cause of morbidity and mortality. With no effective therapy for PE, the only approach to prevent maternal morbidity is delivery. Due to the similarities between PE and cardiovascular disease, we and others have demonstrated the ability of pravastatin (PRA) to reverse several pathophysiologic pathways and phenotypic features of PE. The labeling of PRA as category X is predominantly due to the absence of an indication for its use in pregnancy, as data from experimental animal models and cohorts of pregnant women exposed to PRA early in pregnancy did not support the teratogenicity claims of a category X medication. Recently, as a site in the NICHD-OPRU network and after obtaining an IND from the FDA, we completed a pilot, double-blinded, randomized clinical trial (RCT) of pregnant women at high risk of PE, randomized to 10 mg PRA or placebo. The study revealed favorable maternal-fetal safety and pharmacokinetic (PK) profiles of PRA in this population. The completed pilot trial utilized the lowest dose of PRA (10 mg) allowed in the IND, and our proposed investigation in this application will evaluate PRA at a higher dose (20 mg) already approved by the FDA IND. Our hypothesis is that pravastatin, when given to pregnant women at high risk of PE, exhibits favorable maternal-fetal safety, pharmacodynamics (PD), and PK Profiles. We are proposing a double-blind, placebo- controlled RCT of 100–120 pregnant women at high risk for PE to investigate the following specific aims: (1) determine the maternal-fetal safety profile of PRA during pregnancy, (2) determine whether early prophylactic treatment with PRA in high-risk women reverses the angiogenic imbalance associated with PE, (3) determine the PK of PRA and the formation of its metabolites during pregnancy (compared to the postpartum period), and (4) determine the effects of SNPs in genes encoding uptake and efflux transporters and sulfotransferase enzymes on maternal exposure to PRA. The data obtained on safety, PK parameters, and PD will be compared between the different doses to determine which dose results in the most significant PD effect and the most favorable safety profile. This determination will provide the framework required for the implementation of a larger clinical trial to determine PRA’s ability to prevent PE.