title: A randomized trial to assess the pharmacodynamics and pharmacokinetics of a single dose of an extended-release aspirin formulation.
abstract: OBJECTIVE
  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 Tmax was longer with ER-ASA versus IR-ASA. Administration of IR-ASA resulted in a dose-normalized mean Cmax of ASA that was approximately sixfold higher than that for ER-ASA and a Cmax of SA approximately two- to threefold higher than that for ER-ASA.
  
  
  CONCLUSIONS
  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.
authors.affiliation: New Haven Pharmaceuticals, Inc. , North Haven, CT , USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Patrick
authors.forename: Larry
authors.initials: L
authors.lastname: Dillaha
authors.forename: Danielle
authors.initials: D
authors.lastname: Armas
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001241:Aspirin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002214:Capsules; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D002214:Capsules; D003692:Delayed-Action Preparations; D010975:Platelet Aggregation Inhibitors; D001241:Aspirin
keywords: Acetylsalicylic acid; aspirin; extended release; platelets; thromboxane