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 - 21/11/24

Doi : 10.1016/j.ajog.2024.10.023

Raya Vinogradov, MClinRes ^a,^b,^⁎ , Oisín N. Kavanagh, PhD ^c,^d, Jeremy Palmer, PhD ^d, Paul Murphy, FIBMS ^b, Emma Curtis, MBBS ^b, Farhad Kamali, PhD ^b,^d, Stephen Robson, MD ^a,^b
^a Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
^b Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
^c School of Pharmacy, Newcastle University, Newcastle upon Tyne, UK
^d Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK

^∗Corresponding author: Raya Vinogradov.

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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.

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Key words : aspirin, pharmacodynamics, pharmacokinetics, preeclampsia prevention, pregnancy

Plan

Introduction

Materials and methods

Study design and participants

Sample size calculation

Data analysis

Pharmacokinetic modeling

Pharmacodynamics

Results

Aspirin pharmacokinetics

Aspirin pharmacodynamics

Discussion

Principal findings

Results in the context of what is known

Clinical implications

Research implications

Strengths and limitations

Conclusion

CRediT authorship contribution statement

	R.V. and O.N.K. contributed equally to this manuscript.
	The authors report no conflict of interest.
	S.R. reports financial support was provided by Newcastle Hospitals Charity grant (BF2924). O.N.K. is supported by an Engineering and Physical Sciences Research Council grant (EP/Y014596/1).
	Cite this article as: Vinogradov R, Kavanagh ON, Palmer J, et al. 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. Am J Obstet Gynecol 2024;XXX:XX–XX.
	The study was reviewed by the Wales REC 1 Research Ethics Committee (21/WA/0066) and the MHRA (ref CTA 17136/0292/001-0001) and given favorable opinion on March 30, 2021.
	Date of clinical trial registration: The study was registered with ISRCTN (ISRCTN14693054) on March 09, 2021, EudraCT number 2021-000071-36.
	Date of initial participant enrollment: July 22, 2021.
	Clinical trial identification number: ISRCTN14693054 (the study protocol is publicly accessible on the ISRCTN registry).
	Data availability: Data are available upon request from the corresponding author. To gain access, data requestors will need to sign a data access agreement. Data available: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices), and study protocol. Investigators, who proposed the use of the data, have been approved by an independent review committee.