A randomized crossover design study comparing the pharmacokinetics and pharmacodynamics of 2 single doses of oral aspirin (75 mg v 150 mg) in pregnant women at risk of preeclampsia: implications on assessing aspirin response and patient adherence to therapy

Abstract

Background: Pregnancy is associated with physiological changes that can alter the pharmacokinetic and pharmacodynamic profile of many drugs. Low-dose aspirin is used for preeclampsia 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 2 common doses of aspirin (75 and 150 mg) used for preeclampsia prevention in high-risk women by examining their effect on thromboxane B₂ 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 National Institute for Health and Care Excellence guidance, were recruited into 2×2 randomized crossover trial. Blood samples were collected at baseline, 1, 2, 3, 4, 15, 16, 17, 18, and 19 hours postingestion of either 75 or 150 mg of aspirin with a 7-day washout period. Plasma concentrations of salicylic acid, the primary metabolite of aspirin, were determined using high performance liquid chromatography. Pharmacodynamic response to aspirin was assessed by measuring serum thromboxane B₂ 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. Pharmacokinetic modeling was used to bridge the data arising from the overnight sampling break.

Results: A single dose of 150 mg of aspirin produced higher plasma exposure of SA in comparison to 75 mg (median SA areas under serum SA concentration vs time curve_0-19 16.7 μg∗h/ml [interquartile range 15.2-19.3] vs 6.8 μg∗h/ml [interquartile range 6.1-8.3], P<.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 normalized reduction in serum thromboxane B₂ (median normalized reduction 95.7% [interquartile range 92.6%-97.3%] than the 75-mg dose median normalized reduction 84.6% [interquartile range 77.3%-92.3%], P<.007).

Conclusion: Compared to the 75-mg dose, 150 mg of aspirin more effectively inhibits thromboxane B₂, providing rationale for further investigation of effectiveness of higher doses for preeclampsia prevention. Despite limitations, measuring serum SA concentration could still be used in future models to test adherence if done within 11 to 12 hours after ingestion.

Keywords: aspirin; pharmacodynamics; pharmacokinetics; preeclampsia prevention; pregnancy.