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Pharmacokinetics, Pharmacodynamics, Tolerability, and Safety of the Soluble Guanylate Cyclase Activator Cinaciguat (BAY 58-2667) in Healthy Male Volunteers

From the Departments of Clinical Pharmacology (Dr Frey, Dr Mück, Dr Artmeier-Brandt, Dr Weimann, Dr Wensing) and Global Biostatistics (Ms Unger), Bayer HealthCare AG, Pharma Research Centre, 42096 Wuppertal, Germany.

Preclinical data indicate that the nitric oxide-independent soluble guanylate cyclase activator cinaciguat (BAY 58-2667), which is a new drug in development for patients with heart failure, induces vasodilation preferentially in diseased vessels. This study aimed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of cinaciguat. Seventy-six healthy volunteers were included in this randomized, placebo-controlled study. Cinaciguat (50-250 µg/h) was administered intravenously for up to 4 hours in a maximum of 6 individuals per dose group. No serious adverse events were reported. Four-hour infusions (50-250 µg/h) decreased diastolic blood pressure and increased heart rate (all P values < .05) versus placebo, without significantly reducing systolic blood pressure (P between 0.07 and 0.56). At higher doses (150-250 µg/h), 4-hour infusions decreased mean arterial pressure and increased plasma cyclic guanosine monophosphate levels (all P values < .05). Pharmacokinetics showed dose-proportionality with low interindividual variability. Plasma concentrations declined below 1.0 µg/L within 30 minutes of cessation of infusion. Cinaciguat had potent cardiovascular effects reducing preload and afterload, warranting further investigation in patients with heart failure.

Key Words: Heart failure • cyclic GMP • soluble guanylate cyclase • drug therapy • phase I clinical trial

Address for reprints: Dr Reiner Frey, Department of Clinical Pharmacology, Bayer HealthCare AG, Pharma Research Centre, Aprather Weg 18a, 42096 Wuppertal, Germany; e-mail: reiner.frey{at}bayerhealthcare.com.

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