Abstract
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 B2 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.
- © 2011 ERS