BACKGROUND Pregnancy is associated with physiological changes that can alter the pharmacokinetic and pharmacodynamic profile of many drugs. Low-dose aspirin is used for pre-eclampsia (PE) prevention; however aspirin's pharmacokinetics and pharmacodynamics are poorly studied in pregnant women. OBJECTIVE The aim of this study was to compare the pharmacodynamics of two common doses of aspirin (75 and 150 mg) used for PE prevention in high-risk women by examining their effect on thromboxane B2 (TbxB2) inhibition. A secondary objective sought to assess if salicylic acid could be used as means to evaluate adherence to aspirin. STUDY DESIGN Fourteen pregnant women from a large maternity unit in England, eligible for prophylactic aspirin according to NICE guidance, were recruited into 2 x 2 randomised crossover trial. Blood samples were collected at baseline, 1, 2, 3, 4, 15, 16, 17, 18 and 19-hours post ingestion of either 75 or 150 mg of aspirin with a 7-day washout period. Plasma concentrations of salicylic acid (SA), the primary metabolite of aspirin, were determined using high performance liquid chromatography. Pharmacodynamic response to aspirin was assessed by measuring serum thromboxane B2 (TbxB2) concentrations by an enzyme-linked immunosorbent assay. Analyte data were compared using nonparametric test statistics for paired values (Wilcoxon Signed Rank Test) and areas under serum SA concentration versus time curve (AUC). Pharmacokinetic modelling was used to bridge the data arising from the overnight sampling break. The trial was registered with the ISRCTN (reg number ISRCTN14693054). RESULTS A single dose of 150 mg of aspirin produced higher plasma exposure of SA in comparison to 75 mg (median SA AUC0-19 16.7 μg*h/ml (IQR 15.2-19.3) vs 6.8 μg*h/ml (IQR 6.1- 8.3), p<0.001). Pharmacokinetic models suggest that plasma SA concentrations could be detected above the maximum concentration recorded at baseline for the first 11 hours after 75 mg and for 12 hours after 150 mg aspirin dosing, providing a time frame to confirm recent aspirin ingestion. The 150 mg aspirin dose produced a greater normalised reduction in serum TbxB2 (median normalised reduction 95.7% (IQR 92.6%- 97.3%) than the 75 mg dose (median normalised reduction 84.6% (IQR 77.3-92.3%), p<0.007. CONCLUSION Compared to the 75 mg dose, 150 mg of aspirin more effectively inhibits TbxB2, providing rationale for further investigation of effectiveness of higher doses for pre-eclampsia prevention. Despite limitations, measuring serum SA concentration could still be used in future models to test adherence if done within 11-12 hours after ingestion.

中文翻译：

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一项随机交叉设计研究，比较两种单剂量奥司匹林 （75 mg v 150mg） 在有先兆子痫风险的孕妇中的药代动力学和药效学 （DORA）：对评估阿司匹林反应和患者治疗依从性的影响。


背景 怀孕与生理变化有关，这些变化可以改变许多药物的药代动力学和药效学特征。低剂量阿司匹林用于预防先兆子痫 （PE）;然而，阿司匹林的药代动力学和药效学在孕妇中的研究不足。目的 本研究的目的是通过检查它们对血栓素 B2 （TbxB2） 抑制的影响，比较两种常用剂量的阿司匹林 （75 和 150 mg） 用于预防高危女性 PE 的药效学。次要目的旨在评估水杨酸是否可以用作评估阿司匹林依从性的手段。研究设计 来自英格兰一家大型产科病房的 14 名孕妇，根据 NICE 指南符合预防性阿司匹林的条件，被招募到 2 x 2 随机交叉试验中。在基线、摄入 75 或 150 mg 阿司匹林后 1、2、3、4、15、16、17、18 和 19 小时采集血样，清除期为 7 天。使用高效液相色谱法测定阿司匹林的主要代谢物水杨酸 （SA） 的血浆浓度。通过酶联免疫吸附测定法测量血清血栓素 B2 （TbxB2） 浓度来评估对阿司匹林的药效学反应。使用配对值 （Wilcoxon Signed Rank Test） 和血清 SA 浓度与时间曲线下面积 （AUC） 的非参数检验统计量比较分析物数据。药代动力学模型用于桥接隔夜采样中断产生的数据。该试验已在 ISRCTN 注册（注册号 ISRCTN14693054）。结果与 75 mg 相比，单剂量 150 mg 阿司匹林产生的 SA 血浆暴露更高 （中位 SA AUC0-19 16.7 μg*h/ml （IQR 15.2-19.3） 与 6.8 μg*h/ml （IQR 6.1-8.3），p<0。药代动力学模型表明，在 75 mg 后的前 11 小时和 150 mg 阿司匹林给药后的 12 小时内，可以检测到血浆 SA 浓度高于基线记录的最大浓度，为确认近期阿司匹林摄入提供了时间框架。150 mg 阿司匹林剂量产生的血清 TbxB2 标准化降低幅度更大（中位标准化降低 95.7% （IQR 92.6%-97.3%）比 75 mg 剂量（中位标准化降低 84.6% （IQR 77.3-92.3%）），p<0.007。结论 与 75 mg 剂量相比，150 mg 阿司匹林更有效地抑制 TbxB2，为进一步研究更高剂量预防先兆子痫的有效性提供了理由。尽管存在局限性，但如果在摄入后 11-12 小时内进行，测量血清 SA 浓度仍可用于未来的模型，以测试依从性。