No pharmacodynamic (PD) and pharmacokinetic (PK) interaction of riociguat (BAY 63-2521) and aspirin

Objectives: Riociguat, an oral soluble guanylate cyclase (sGC) stimulator, is a new candidate for treatment of pulmonary hypertension (PH). Riociguat increases cGMP production through a novel dual mode of action: direct NO-independent stimulation of sGC; and increasing sensitivity of sGC to low levels of NO. Riociguat and aspirin are likely to be used together in PH. This randomized, open-label, crossover study investigated potential PD and PK interactions between the 2 drugs. Methods: Participants took 2.5 mg/day riociguat, two morning doses of 500 mg aspirin, or both treatments concomitantly. Results: Eighteen healthy men (mean age 34.8 years) were enrolled. Six of 17 participants in the safety evaluation reported ≥1 treatment-emergent adverse event (AE). All AEs were mild except 1 case of moderate headache following riociguat administration. Fifteen participants were valid for PD/PK analysis. Riociguat PK were independent of aspirin coadministration. One hour after coadministration of riociguat and aspirin, the mean increase in fraction unbound was 19% for riociguat and 24% for its metabolite M-1 (BAY 60-4552) indicating mild displacement by salicylic acid, the main aspirin metabolite. Effects of aspirin on bleeding time, platelet aggregation and plasma thromboxane B 2 were not affected by concomitant riociguat. Riociguat alone had no effect on PD variables. Conclusion: Riociguat demonstrated no clinically relevant PD or PK interaction with aspirin. Coadministration of riociguat and aspirin does not require dose adjustment. Phase 3 randomized controlled trials are investigating riociguat in chronic thromboembolic pulmonary hypertension or pulmonary arterial hypertension.