Pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase activator cinaciguat (BAY 58-2667) in healthy male volunteers.
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 microg/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 microg/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 microg/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 microg/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.
Frey
Reiner
R
Department of Clinical Pharmacology, Bayer HealthCare AG, Pharma Research Centre, Aprather Weg 18a, 42096 Wuppertal, Germany. reiner.frey@bayerhealthcare.com
Mück
Wolfgang
W
Unger
Sigrun
S
Artmeier-Brandt
Ulrike
U
Weimann
Gerrit
G
Wensing
Georg
G
D000328:Adult; D000804:Angiotensin II / Q000097:blood; D019540:Area Under Curve; D001565:Benzoates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000097:blood; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006162:Guanylate Cyclase / Q000378:metabolism*; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D009638:Norepinephrine / Q000097:blood; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012083:Renin / Q000097:blood / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase; D016896:Treatment Outcome; D055815:Young Adult
D001565:Benzoates; D020536:Enzyme Activators; D018160:Receptors, Cytoplasmic and Nuclear; D000804:Angiotensin II; C480588:BAY 58-2667; D012083:Renin; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D009638:Norepinephrine