PK OF LMWH AND UFH IN PREGNANCY

妊娠期间 LMWH 和 UFH 的 PK

• 批准号: 7604778
• 负责人: MARY D STEPHENSON
• 金额: $ 0.2万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2007-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7604778
• 关键词: Age; Analysis of Variance; Antiphospholipid Syndrome; Area; Blood Clot; Blood coagulation; Blood specimen; Cessation of life; Cities; Complication; Computer Retrieval of Information on Scientific Projects Database; Computer software; Condition; Dalteparin; Diagnostic; Disease; Dose; Drug Kinetics; Equilibrium; Event; Exhibits; Funding; Grant; Half-Life; Heparin; Individual; Inherited; Institution; KLK3 gene; Laboratories; Low-Molecular-Weight Heparin; Measures; Methodology; Microcomputers; Modeling; Patient currently pregnant; Pharmacodynamics; Philadelphia; Population Study; Postpartum Period; Pregnancy; Pregnant Women; Principal Investigator; Procedures; Protocols documentation; Randomized Controlled Clinical Trials; Recording of previous events; Regression Analysis; Research; Research Personnel; Residual state; Resources; Risk; Sodium Chloride; Source; Specialist; Study Subject; Sum; Thromboembolism; Thrombophilia; Time; United States National Institutes of Health; Venous; Week; Woman; base; desire; pharmacodynamic model; programs

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVES To determine, through pharmacokinetic parameters, the ideal dosing protocol for dalteparin (a low molecular weight heparin) and unfractionated heparin (UFH) for women desiring pregnancy who have evidence of an acquired (specifically, antiphospholipid syndrome) or inherited thrombophilia. BACKGROUND The most common cause of maternal death in pregnancy is thromboembolic disease (i.e. blocking of vessels by blood clot). The risk of venous thromboembolism is five times greater in pregnant vs. age-matched non-pregnant women. In addition, women with a previous history of a thromboembolic event have a significantly increased risk of another thromboembolic complication during pregnancy. Dr. Stephenson (Principal Investigator) and Dr. Ensom (Sub-Investigator) conducted a previous randomized trial, in which women with APS desiring pregnancy received either dalteparin or unfractionated heparin. Based on the results of this pilot pharmacokinetic study, dosing protocols have been revised, which now need to be verified. METHODOLOGY Individual study subjects will participate in the study prior to and throughout their pregnancy, as well as postpartum. The study population will consist of 10 subjects prescribed dalteparin and 10 subjects prescribed UFH (20,000 units/mL). Research Protocol: Study procedures will consist of serial blood sampling (over a 12h and 24h period for UFH and LMWH, respectively) under steady-state conditions during the pre-pregnant state and the 1st (9-11 weeks), 2nd (22-24 weeks), and 3rd (34-36 weeks) trimesters and postpartum, to characterize heparin pharmacokinetics and pharmacodynamics. Pharmacokinetic and pharmacodynamic modeling: Pharmacokinetic parameters [area under the concentration time curve (AUC), maximal (Cmax), minimal (Cmin), and mean concentrations, and elimination half-life (t1/2)] will be calculated by traditional noncompartmental (PHARM/PCS, MicroComputer Specialists, Philadelphia, PA), compartmental (PKAnalyst, MicroMath Scientific Software, Salt Lake City, UT) and Bayesian (Abbottbase Pharmacokinetics Program, Abbott Laboratories, Diagnostic Div., Irving, TX) analyses. The best dosing strategy (i.e. best model selected) will be the one exhibiting the best balance between a modified Akaike information criterion value, residual sum of squares, and coefficient of determination. Statistical analysis: Two-factor repeated measures analysis of variance will be used to determine within group (UFH and LMWH, respectively) and between group (UFH vs. LMWH) differences over time (pre-pregnancy, each trimester and post-pregnancy). Linear regression analysis will be used to assess relationships between continuous variables (e.g. dose vs. APTT, etc.).

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目标 通过药代动力学参数，确定达特肝素(一种低分子肝素)和普通肝素(UFH)对于有获得性(特别是抗磷脂综合征)证据或遗传性血栓形成的妇女的理想剂量方案。 背景 妊娠期间产妇死亡的最常见原因是血栓栓塞症(即血栓阻塞血管)。与年龄匹配的非怀孕妇女相比，怀孕妇女发生静脉血栓栓塞症的风险高出五倍。此外，既往有血栓栓塞史的妇女在怀孕期间发生另一次血栓栓塞症并发症的风险显著增加。 斯蒂芬森博士(首席调查员)和恩索姆博士(副调查员)进行了一项先前的随机试验，在该试验中，希望怀孕的APS妇女接受达替肝素或普通肝素治疗。根据这项先导性药代动力学研究的结果，给药方案已经修订，现在需要验证。 方法论 个别研究对象将在怀孕前和整个怀孕期间以及产后参与这项研究。研究人群将包括10名服用达肝素的受试者和10名服用UFH(20000单位/毫升)的受试者。 研究方案：研究程序将包括在妊娠前和妊娠第1周(9-11周)、第2周(22-24周)和第3周(34-36周)的稳态条件下连续采血(UFH和LMWH分别在12小时和24小时内)，以表征肝素的药代动力学和药效学。 药代动力学和药效学模型：药代动力学参数[在浓度时间曲线下的面积(AUC)、最大浓度(Cmax)、最小浓度(Cmin)和平均浓度，以及消除半衰期(T1/2)]将通过传统的非隔室分析(Pharm/PCS，Philadelphia，PA)、隔室分析(PKAnalyst，MicroMath Science Software，盐湖城，德克萨斯州)和贝叶斯分析(Abbottbase药代动力学计划，雅培实验室，诊断科，欧文，德克萨斯州)来计算。最佳剂量策略(即所选择的最佳模型)将是在修正的Akaike信息标准值、残差平方和和确定系数之间表现出最佳平衡的策略。 统计分析：将使用双因素重复测量方差分析来确定组内(UFH和LMWH分别)和组间(UFH与LMWH)随时间(孕前、每三个月和孕后)的差异。将使用线性回归分析来评估连续变量之间的关系(例如，剂量与APTT等)。