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

  title={Pharmacokinetics, Pharmacodynamics, Tolerability, and Safety of the Soluble Guanylate Cyclase Activator Cinaciguat (BAY 58‐2667) in Healthy Male Volunteers},
  author={Reiner Frey and Wolfgang M{\"u}ck and Sigrun Unger and Ulrike Artmeier-Brandt and Gerrit Weimann and Georg Wensing},
  journal={The Journal of Clinical Pharmacology},
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… 

Population Pharmacokinetics and Pharmacodynamics of Cinaciguat, a Soluble Guanylate Cyclase Activator, in Patients with Acute Decompensated Heart Failure

Intravenously administered cinaciguat had predictable pharmacokinetic and haemodynamic effects in patients with ADHF.

A Randomized, Placebo‐Controlled, Multiple‐Ascending‐Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Soluble Guanylate Cyclase Stimulator Praliciguat in Healthy Subjects

Results support evaluation of praliciguat for the treatment of conditions associated with deficient NO signaling, and dose proportional Pharmacokinetics were dose proportional, with an effective half‐life of 24–37 hours, supporting once‐daily dosing.

Safety, Pharmacokinetics, and Pharmacodynamics of TD‐0714, a Novel Potent Neprilysin Inhibitor in Healthy Adult and Elderly Subjects

The TD‐0714 PK and PD profiles support further clinical development of TD‐714 and suggest the potential for once‐daily administration and predictable exposure in patients with cardiorenal diseases regardless of their renal function.

Cinaciguat, a soluble guanylate cyclase activator, unloads the heart but also causes hypotension in acute decompensated heart failure.

Cinaciguat unloaded the heart in patients with ADHF, however, high doses were associated with hypotension and the trial was stopped prematurely due to an increased occurrence of hypotension at cinacigsuat doses ≥200 µg/h.

Assessment of the Effects of Renal Impairment on the Pharmacokinetics of the Soluble Guanylate Cyclase Activator Cinaciguat After a Single Intravenous Dose

Cinaciguat, a promising drug candidate for the treatment of acute decompensated heart failure, will not require dose adjustment based on renal function, and its pharmacokinetic variability tended to be somewhat increased in individuals with renal impairment.

Pharmacokinetics of the Soluble Guanylate Cyclase Activator Cinaciguat in Individuals With Hepatic Impairment

It is demonstrated that in individuals with mild hepatic impairment, individual dose adaptation may not be required and cinaciguat was well tolerated and had a favorable safety profile.

Cinaciguat (BAY 58–2667) Improves Cardiopulmonary Hemodynamics in Patients With Acute Decompensated Heart Failure

Cinaciguat has potent preload- and afterload-reducing effects, increasing cardiac output and well tolerated, with 13 of 60 patients reporting 14 drug-related treatment-emergent adverse events of mild to moderate intensity.

A novel soluble guanylate cyclase activator with reduced risk of hypotension by short‐acting vasodilation

TY‐55002 is a novel short‐acting sGC activator, which offers the possibility of easy dose management without excessive hypotension and holds potential to serve as an innovative drug in the pharmacotherapy of ADHF.

Cinaciguat (BAY-582667) Modifies Cardiopulmonary and Systemic Circulation in Chronically Hypoxic and Pulmonary Hypertensive Neonatal Lambs in the Alto Andino

Cinaciguat, an activator of sGC, induces cardiopulmonary modifications in chronically hypoxic and pulmonary hypertensive newborn lambs and is a potential therapeutic tool for reducing pulmonary vascular remodeling and/or right ventricular hypertrophy in pulmonary arterial hypertension syndrome.

Role of guanylate cyclase modulators in decompensated heart failure

Preliminary studies of cinaciguat in patients with acute decompensated heart failure show substantial improvements in haemodynamics and symptoms, whilst maintaining renal function.



Cardiovascular effects of the soluble guanylyl cyclase activator BAY 58–2667 in anesthetized dogs

Beagle dogs anesthetized withneuroleptic anesthesia with droperidol/fentanyl and artificially ventilated with sham treatment and total peripheral resistance was calculated as mean arterial pressure (BPM) divided by cardiac output.

Targeting Heme-Oxidized Soluble Guanylate Cyclase in Experimental Heart Failure

Beneficial properties make direct soluble guanylate cyclase stimulation with BAY 58-2667 a promising new therapeutic strategy for cardiovascular diseases, such as heart failure.

Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels.

It is shown in vivo that oxidative stress and related vascular disease states, including human diabetes mellitus, led to an sGC that was indistinguishable from the in vitro oxidized/heme-free enzyme, and BAY 58-2667 was more effective and potentiated under pathophysiological and oxidative stress conditions.

NO‐ and haem‐independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle

A novel type of sGC activator which activates the enzyme even after it has been oxidized by the sGC inhibitor ODQ or rendered haem deficient is identified and may offer a new approach for treating cardiovascular diseases.

Targeting heme-oxidized soluble guanylate cyclase: solution for all cardiorenal problems in heart failure?

Experimental and clinical studies revealed that NO production is decreased because of decreased expression of endothelial NO synthase and diminished endothelial No synthase–mediated NO production, which is probably an important reason for increased vascular resistance and afterload in heart failure.

NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential

The discovery, biochemistry, pharmacology and clinical potential of haem-dependent sGC stimulators andHaem-independent sGC activators are reviewed.

Design and synthesis of the first NO- and haem-independent sGC activator BAY 58–2667 for the treatment of acute decompensated heart failure

Compounds that activate sGC in an NO-independent manner might provide considerable therapeutic advantages, including non-specific interactions of NO with various biomolecules and lack of response and the development of tolerance.

Acute Decompensated Heart Failure: A Contemporary Approach to Pharmacotherapeutic Management

Experimental agent levosimendan is a positive inotropic agent but does not increase myocyte calcium concentrations as do catecholamines or phosphodiesterase inhibitors, but clinical trial evidence demonstrates a positive survival benefit for levosIMendan versus dobutamine.

Side effects of using nitrates to treat heart failure and the acute coronary syndromes, unstable angina and acute myocardial infarction

No such adverse effects of nitrates have been reported in the large randomized trials in patients with acute myocardial infarction or chronic heart failure, despite the disturbing observational reports in the literature.

Management of acute decompensated heart failure

Few agents currently available for the treatment of acute decompensated heart failure have been definitively shown in large prospective randomized clinical trials to provide meaningful improvements in intermediate-term clinical outcomes.