Antiplatelet effects of aspirin are not affected by the soluble guanylate cyclase activator cinaciguat (BAY 58-2667)

IntroductionCinaciguat (BAY 58-2667) is an nitric oxide (NO)-inde-pendent and heme-independent soluble guanylatecyclase (sGC) activator. Cinaciguat preferentially acti-vates sGC in its oxidized or heme-free state, when theenzyme is insensitive to its endogenous ligand NO andexogenous nitrovasodilators [1].Endothelium-derived NO is one of the mechanisms bywhich platelet aggregation and thrombus formation isprevented by the intact blood vessel wall. Pharmacologi-cal stimulation of sGC in platelets correlates with inhibi-tion of aggregation, platelet cGMP increase, prolongationof bleeding time and antithrombotic effects in vitro [2].This protective mechanism may be impaired in vasculardisease and impaired NO availability. Thus, sGC activa-tors may have antithrombotic effects similar to endogen-ous NO. Indeed, cinaciguat potently inhibited plateletaggregation induced by the thromboxane mimic U46619and collagen and prolonged rat-tail bleeding time up to2-fold [3]. Thus, in vitro data suggested that coadminis-tration of cinaciguat and aspirin may increase the antipla-telet effects of aspirin and could result in bleeding.MethodsThis non-randomized, open-label trial was conductedfrom September to November 2001 in a single center inGermany. It was carried out in accordance with theDeclaration of Helsinki and adhered to the InternationalConference of Harmonization good clinical practiceguidelines and the German drug law (AMG). The studyprotocol was approved by the Ethics Committee of theNorth-Rhine Medical Council, Duesseldorf, Germany.The study consisted of a 9-day treatment phase with100 mg oral acetylsalicylicacid (aspirin) once dailyadministered in the morning in the fasting state and,after the last dose of aspirin, four sequential oral dosesof 1.5 mg cinaciguat administered in the fasting state at1-hour intervals. The first dose of cinaciguat was admi-nistered together with the last dose of aspirin. This cina-ciguat dosing schedule was used to mimic a prolongedplasma concentration over time profile.Results12 healthy men (mean age, 32.4 years, range, 23 - 42years) were enrolled and completed the study accordingto protocol.Low-dose aspirin treatment in healthy subjectsresulted in the expected inhibition of platelet aggrega-tion. 4 oral doses of 1.5 mg cinaciguat administered at1-hour intervals did not significantly affect plateletaggregation induced by collagen and the thromboxaneA2 mimetic U 46619 or bleeding time. These results arein line with the findings of a single dose escalationstudy.Plasma pharmacokinetics of cinaciguat following 4oral doses of 1.5 mg cinaciguat administered at 1-hourintervals showed pronounced inter-individual variability.There was no major pharmacokinetic interactiondetected between aspirin and cinaciguat, compared withthe data of a previous study, which applied the samedosing regimen.ConclusionCoadministration of cinaciguat and aspirin did notreveal any pharmacodynamic interaction with respect of