A randomised crossover design study comparing the pharmacokinetics and pharmacodynamics of two single Doses of ORal Aspirin (75 mg v 150mg) in pregnant women at risk of pre-eclampsia (DORA): implications on assessing aspirin response and patient adherence to therapy.

Abstract

BackgroundPregnancy 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. ObjectiveThe 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 DesignFourteen 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). ResultsA 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. ConclusionCompared 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.