PK OF LMWH AND UFH IN PREGNANCY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目标 通过药代动力学参数确定达肝素（一种低分子量肝素）和普通肝素（UFH）用于有获得性（特别是抗磷脂综合征）或遗传性血栓形成倾向证据的希望怀孕的女性的理想给药方案。 背景 孕妇死亡的最常见原因是血栓栓塞性疾病（即血块阻塞血管）。 静脉血栓栓塞的风险是五倍，在怀孕与年龄匹配的非怀孕妇女。 此外，既往有血栓栓塞事件史的女性在妊娠期间发生另一种血栓栓塞并发症的风险显著增加。 博士斯蒂芬森（主要研究者）和Ensom博士（助理研究者）进行了一项既往随机试验，其中希望妊娠的APS女性接受达肝素或普通肝素治疗。 根据这项初步药代动力学研究的结果，对给药方案进行了修订，现在需要进行验证。 方法 个体研究受试者将在妊娠前、妊娠期间以及产后参与研究。 研究人群将包括10例接受达肝素治疗的受试者和10例接受UFH（20，000单位/mL）治疗的受试者。 研究方案：研究程序将包括在妊娠前状态和妊娠第1（9-11周）、第2（22-24周）和第3（34-36周）以及产后稳态条件下的连续采血（UFH和LMWH分别为12小时和24小时），以表征肝素药代动力学和药效学。 药代动力学和药效学建模：药代动力学参数[浓度下面积 时间曲线（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）]将通过传统非房室模型（PHARM/PCS，MicroComputer Specialists，Philadelphia，PA）、房室模型（PKAnalyst，MicroMath Scientific Software，湖城，UT）和贝叶斯模型（Abbottbase Pharmacokinetics Program，Abbott Laboratories，Diagnostic Div.，欧文，TX）分析。 最佳给药策略（即选择的最佳模型）将是在改良的Akaike信息标准值、残差平方和决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确定组内（分别为UFH和LMWH）和组间（UFH与LMWH）随时间（妊娠前、每个妊娠期和妊娠后）的差异。 将使用线性回归分析评估连续变量之间的关系（例如，剂量与APTT等）。

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.).