Pharmacokinetics and pharmacodynamics of acethylsalicylic acid in high-risk pregnancy (ASAP)
Progetto Background. Excessive production of thromboxane A2 (TxA2), a vasoconstrictor and agonist of platelet aggregation, and reduced production of prostacyclin, a vasodilator and inhibitor of platelet aggregation, occur in pre-eclampsia. These observations stimulated interest in pre-eclampsia prevention by acetylsalicylic acid (ASA), which inhibits platelet TxA2-mediated vasoconstriction and formation of platelet thrombi. Randomized trials of ASA in pre-eclampsia prevention gave contradictory results. Meta-analyses demonstrated a protective effect of low-dose ASA (50-150 mg) given before the 16th week of gestation. Consequently, guidelines suggest to use low dose ASA beginning before week 16 of gestation in high-risk pregnancies. The lower than expected protection could be explained by sub-optimal pharmacodynamics (PD) of ASA (“ASA resistance”), caused by: 1) prevalent use of enteric-coated ASA, whose pharmacokinetics (PK) and PD are less efficient than those of plain ASA; 2) altered ASA absorption, distribution and metabolism caused by physiological changes in pregnancy. The choice of the laboratory test to identify “ASA resistance” is critical, as global tests of primary haemostasis, unspecific for TxA2, may overestimate its prevalence. Measurement of serum levels of TxB2 (TxA2 metabolite) is the most accurate test for ASA PD.
Objectives. Primary objective of our superiority study is to test whether the prevalence of “ASA resistance” is higher among pregnant women (cases) than in age- and body mass index (BMI)-matched healthy, non-pregnant women (controls). Secondary objectives will be to compare PK and PD of enteric-coated and plain ASA in cases and controls.
Methods. Assuming a prevalence of “ASA resistance” in controls of 2.0%, enrolment of 62 matched pairs will provide 80% power to detect 15.0% absolute increase of the prevalence, at a two-sided significance level of 0.05. Allowing 10% withdrawal from the study, the calculated sample size is 70 pairs. All pregnant women at high risk for pre-eclampsia will be prescribed enteric-coated ASA (100 mg od). During each of the periods comprised between weeks 12-16, 20-24 and 32-36, cases will undergo two visits. During the first visit in each period, blood samples will be taken for ASA PK/PD studies 24 h after the last drug intake. Then, women will be given the daily tablet of 100 mg enteric-coated ASA and undergo further blood sampling after 1,2,3,4,5,6 hours. Treatment will then be switched to the same dose of plain ASA, starting the day after, for the following 13 days. On day 14, pregnant women will undergo the second visit, with identical procedures as during the first visit. Controls will undergo the same treatment protocol as cases, with the exceptions that: 1) both treatments will last 14 days; 2) treatments and PK/PD measurements will take place once. Laboratory tests will include measurements of: 1) ASA and salicylic acid plasma concentrations by Liquid Chromatography/Tandem Mass Spectrometry; 2) serum TxB2 levels by enzyme immunoassay; 3) circulating activated (P-selectin expressing) platelets by flow-cytometry.
Expected results. The study will provide information on PK/PD of 100 mg enteric-coated ASA in pregnancy. If, as expected, the results of our study will prove that PK/PD profile of plain ASA is preferable to that of enteric-coated ASA in pregnant women, they would provide sufficient evidence for recommending plain ASA for pre-eclampsia prevention, because better PK/PD profile likely results in greater clinical efficacy. This would increase the cost effectiveness of the prevention strategy, because the cost of the two ASA formulations is similar.