目的:我们试图描述阿司匹林在整个妊娠(妊娠早期和妊娠晚期)的药代动力学和药效学,确定显著影响阿司匹林药代动力学(PK)的协变量,并确定阿司匹林药代动力学和药效学(PD)之间的关系。
方法:这是一项针对子痫前期高危患者的前瞻性研究,建议每天服用81mg阿司匹林。本研究涉及三次访视:基线:妊娠早期(10-16周)6小时PK访视,在开始服用阿司匹林之前进行;随访-1:开始服用阿司匹林后2-4周;随访-2:妊娠晚期6小时PK访视(28-32周)。每次访视时评估以下内容:体重/BMI,PFA-100(西门子),尿血栓素B2(TX-B2),血清血栓素B2(TX-B2)和血浆水杨酸。PK访视包括基线时(给药前)的血液检查,服用81mg非肠溶阿司匹林,然后在给药后30分钟和每小时1-6小时评估水杨酸的血浆血液水平。使用皮尔逊相关性和多变量回归来识别参数之间的关联并识别相关的协变量。用于回归分析的对数调整值。P<0.05认为是显著的。
结果:19名参与者纳入了孕早期数据,和16个妊娠晚期数据。在妊娠早期和晚期之间,平均PK参数没有统计学上的显着变化,尽管在第3个月和第1个月有降低Cmax的趋势(p=0.08)。在多变量回归中,基线肥胖和作为连续测量的当前BMI与对数调整的峰值水杨酸浓度呈负相关(-0.28(-0.46--0.11),p=0.003和-0.02(-0.03--0.009),分别为p=0.001)和对数调整后的血浆水杨酸面积(AUC0-6)(-0.25(-0.45-0.05),p=0.02,-0.04(-0.07--0.01),p分别=0.008)。与基线相比,阿司匹林开始后2-4周的尿血栓素显著减少,与PFA-100闭合时间的增加相关。在多元回归模型中,血浆水杨酸浓度(给药后0-6小时的曲线下面积)和尿血栓素(B=-3.12(-5.38--1.04)之间有很强的相关性,p=0.006),尿中血栓素抑制和血小板抑制,PFA-100(-0.23(-0.31--0.14),p<0.001)。随着血栓烷的逐步抑制,血小板抑制(PFA-100闭合时间)增加。个人合并症,包括体重,高血压,糖尿病,也影响了阿司匹林的反应。
结论:我们已经证明了个体因素之间的关系,水杨酸的血浆浓度,血栓烷抑制,在整个怀孕期间服用单剂量(81毫克)阿司匹林和血小板抑制。我们的发现表明,在怀孕期间调整阿司匹林的剂量可能有助于达到最佳反应。我们的结果可用于促进计算建模,以在考虑个体因素的情况下确定最佳剂量。
BACKGROUND: Low dose aspirin is recommended for prevention of preeclampsia, however there is not consensus on the appropriate dose. Pregnancy specific changes have the potential to impact the pharmacology of aspirin in pregnancy, however there are very limited studies on aspirin pharmacokinetics in pregnancy and none linking pharmacokinetics (PK, drug dose and drug level) to pharmacodynamics (PD, drug dose and physiologic response) in pregnancy. As a result, we do not have a good understanding of the pharmacologic response to aspirin in pregnancy, which has important implications for clinical efficacy. We sought to describe the PK and PD of aspirin through pregnancy and to identify individual covariates that impacted aspirin PK/PD.
OBJECTIVE: We sought to describe the PK and PD of aspirin through pregnancy (first and third trimester), to identify covariates that significantly impact aspirin PK and to identify the relationship between aspirin PK and PD.
METHODS: This is a prospective study of patients at high risk for preeclampsia recommended to take 81 mg aspirin daily. This study involved 3 visits as follows: (1) baseline, first trimester (10-16 weeks of gestation) 6-hour PK visit, done before initiation of aspirin; (2) follow-up 1: 2 to 4 weeks after aspirin initiation; and (3) follow-up 2: third trimester 6-hour PK visit (28-32 weeks of gestation). The following were assessed at each visit: weight or body mass index, platelet function analysis-100 (Siemens), urinary thromboxane B2, serum thromboxane B2, and plasma salicylic acid. The PK visits consisted of blood work done at baseline (predose), administration of 81 mg nonenteric coated aspirin, and then plasma blood level of salicylic acid assessed at 30 minutes and then hourly 1 to 6 hours after dose. Pearson correlation and multivariable regression were used to identify associations between parameters and identify relevant covariates. Log-adjusted values were used for regression analysis. P<.05 was considered statistically significant.
RESULTS: Nineteen participants were included with first trimester data, and 16 with third trimester data. There was no statistically significant change in mean PK parameters between the first and third trimester, although there was a trend to lower peak concentration in the third than in the first trimester (P=.08). In multivariable regression, baseline obesity and current body mass index as a continuous measures were negatively associated with log-adjusted peak salicylic acid concentration (-0.28 [-0.46 to -0.11], P=.003 and -0.02 [-0.03 to -0.009], P=.001, respectively) and log-adjusted plasma salicylic acid area under the curve 0 to 6 hours postdose (-0.25 [-0.45 to 0.05], P=.02, -0.04 [-0.07 to -0.01], P=.008 respectively). There was a significant decrease in urinary thromboxane 2 to 4 weeks after aspirin initiation compared with baseline, which correlated with a concomitant increase in platelet function analysis-100 closure time. In multivariable regression model, there was a strong association between plasma salicylic acid concentration (area under the curve 0-6 hours postdose) and urinary thromboxane (B=-3.12 [-5.38 to -1.04], P=.006), and with urinary thromboxane suppression and platelet inhibition, platelet function analysis-100 (-0.23 [-0.31 to -0.14], P<.001). With progressive thromboxane suppression, platelet inhibition (platelet function analysis-100 closure time) increased. Individual comorbidities, including weight, hypertension, and pregestational diabetes (Type I or II), also impacted aspirin response.
CONCLUSIONS: We have demonstrated the relationship between individual factors, plasma concentrations of salicylic acid, thromboxane suppression, and platelet inhibition at a single dose (81 mg) of aspirin taken through pregnancy. Our findings suggest that dose modification of aspirin in pregnancy may help to achieve the optimal response. Our results may be used to facilitate computational modeling to identify optimal dosing, taking into consideration individual factors.