A randomized trial to assess the pharmacodynamics and pharmacokinetics of a single dose of an extended-release aspirin formulation

Abstract

Aims. Low-dose acetylsalicylic acid (ASA; aspirin) for secondary prevention reduces cardiovascular disease mortality risk. ASA acetylates cyclooxygenase in the portal circulation and is rapidly (half-life, 20 min) hydrolyzed. Certain patients with cardiovascular disease may exhibit high on-therapy platelet reactivity as a result of high platelet turnover, a process whereby platelets are produced and are active beyond the duration of antiplatelet coverage provided by once-daily immediate-release (IR) ASA. A once-daily, extended-release (ER) ASA formulation using ER microcapsule technology was developed to release ASA over the 24-h dosing interval and reduce maximal plasma concentrations to spare peripheral endogenous endothelial prostacyclin production. Methods. Healthy adults (n = 50) were randomized in a crossover study to receive two different ER-ASA single doses (up to 325 mg) and two different IR-ASA single doses (up to 81 mg) in four periods, each separated by ≥14 days. Pharmacodynamics was assessed by measuring serum thromboxane B₂ (TXB₂), urine 11-dehydro-TXB₂, and arachidonic acid-induced platelet aggregation. Pharmacokinetics was determined for ASA and salicylic acid (SA). Results: Both formulations produced dose-dependent inhibition on all pharmacodynamic parameters. Marked inhibition of TXB₂ and 11-dehydro-TXB₂ was maintained over the 24-h dosing interval after a dose of ≥81 mg ER-ASA or ≥40 mg IR-ASA. The dose required to achieve 50% of maximum TXB₂ inhibition with ER-ASA was 49.9 mg versus 29.6 mg for IR-ASA, for a similar maximum pharmacodynamic effect (98.9% TXB₂ inhibition). This suggests that an approximately twofold greater ER-ASA dose (162.5 mg) is necessary to obtain the same response as that of IR-ASA 81 mg. Peak ASA concentrations were lower and T_max was longer with ER-ASA versus IR-ASA. Administration of IR-ASA resulted in a dose-normalized mean C_max of ASA that was approximately sixfold higher than that for ER-ASA and a C_max of SA approximately two- to threefold higher than that for ER-ASA. Conclusion. Both ASA formulations showed dose-dependent antiplatelet activity. Compared with the IR-ASA, ER-ASA released active drug more slowly, resulting in prolonged absorption and lower systemic drug concentrations, which is expected for an ER (24-h) formulation.

Keywords :

• Acetylsalicylic acid
• aspirin
• extended release
• platelets
• thromboxane

Declaration of interest

This study was supported by New Haven Pharmaceuticals, Inc. Technical editorial and medical writing support, under direction of the authors, was provided by Mary Beth Moncrief, PhD, and Michael Shaw, PhD, Synchrony Medical Communications, LLC, West Chester, PA, USA, with support from New Haven Pharmaceuticals Inc. J Patrick and L Dillaha are employees of New Haven Pharmaceuticals. D Armas is an employee of Celerion, a company that received support from New Haven Pharmaceuticals for conducting this study. WC Sessa oversees a scientific advisory board for New Haven Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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