Riociguat (BAY 63‐2521) and Aspirin: A Randomized, Pharmacodynamic, and Pharmacokinetic Interaction Study

Abstract

In preclinical studies, drugs that increase cyclic guanosine monophosphate levels have been shown to influence platelet function/ aggregation; however, the effect of riociguat on human platelets is unclear. Aspirin, a platelet inhibitor, is likely to be given concomitantly in patients receiving riociguat. It is therefore important to establish clinically whether (1) riociguat affects platelet function and (2) aspirin and riociguat interact. This randomized, open-label, crossover study investigated potential pharmacodynamic and pharmacokinetic interactions between these drugs in healthy male volunteers (N = 18). There were 3 treatment regimens: a single morning dose of riociguat 2.5 mg, aspirin 500 mg on 2 consecutive mornings, and both treatments together, with riociguat given on the second morning. Fifteen participants were available for pharmacodynamic/pharmacokinetic analysis. There was no effect of riociguat alone on bleeding time, platelet aggregation, and serum thromboxane B 2 levels. The effects of aspirin on these parameters were not influenced by concomitant administration of riociguat. The pharmacokinetic profile of riociguat showed interindividual variability, which was independent of aspirin coadministration. Six of 17 participants available for safety evaluation reported at least 1 treatment-emergent adverse event. All adverse events were of mild severity, apart from 1 report of moderate headache. No serious adverse events occurred. In conclusion, riociguat demonstrated no clinically relevant pharmacodynamic or pharmacokinetic interactions with aspirin at the doses used in this study in healthy men; coadministration of riociguat and aspirin should therefore not require any dose adjustment for either drug.

A focus on riociguat in the treatment of pulmonary arterial hypertension

“…Riociguat has been shown to have only a weak interaction with drug‐metabolizing enzymes and drug transporters, why it is less likely to be a precipitant drug . Riociguat has been tested in combination with both warfarin and aspirin, and no relevant clinical interactions have been found . CYP3A4 and P‐glycoprotein inhibitors such as ketoconazole or clarithromycin may lead to an increased plasma concentration of riociguat and to hypotension .…”

“…38 Riociguat has been tested in combination with both warfarin and aspirin, and no relevant clinical interactions have been found. 39,40 CYP3A4 and P-glycoprotein inhibitors such as ketoconazole or clarithromycin may lead to an increased plasma concentration of riociguat and to hypotension. 38 Importantly, the PAH treating drug bosentan is a CYP34A/P-glycoprotein inductor and may lead to reduced plasma concentration of riociguat.…”

Clinical Pharmacokinetic and Pharmacodynamic Profile of Riociguat

“…Coadministration of warfarin (25 mg) did not significantly alter riociguat AUC τ ,ss (estimated ratio 96%). Further riociguat dose adjustment beyond the individual dose-adjustment scheme is not necessary Acetylsalicylic acid [ 49 ] No relevant difference Pre- and coadministration of acetylsalicylic acid (500 mg qd) did not significantly alter riociguat AUC ∞ (estimated ratio 96%). Riociguat did not potentiate the effect of acetylsalicylic acid on bleeding time or platelet aggregation.…”

“…In patients with PAH, acetylsalicylic acid might be administered at a low dose for anticoagulant activity, or at a high dose for pain relief. The potential of riociguat to increase the anti-aggregatory effect of acetylsalicylic acid was therefore evaluated [ 49 ]. In healthy individuals, the effects of acetylsalicylic acid 500 mg on bleeding time, platelet aggregation, and serum thromboxane B 2 levels were not influenced by coadministration of riociguat 2.5 mg.…”

“…In healthy individuals, the effects of acetylsalicylic acid 500 mg on bleeding time, platelet aggregation, and serum thromboxane B 2 levels were not influenced by coadministration of riociguat 2.5 mg. Thus, no clinically relevant pharmacodynamic interaction between riociguat and acetylsalicylic acid was detected [ 49 ].…”