Reiner Frey

Single-Dose Pharmacokinetics, Pharmacodynamics, Tolerability, and Safety of the Soluble Guanylate Cyclase Stimulator BAY 63-2521 : An Ascending-Dose Study in Healthy Male Volunteers

The aim of the study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of BAY 63–2521, a new drug in development for pulmonary hypertension. Fifty‐eight healthy male volunteers received a single oral dose of BAY 63–2521 (0.25–5 mg) or placebo. No serious adverse events were reported; there were no life‐threatening events. Heart rate over 1 minute, an indicator of the effect of a vasodilating agent on the cardiovascular system in healthy subjects, was increased dose dependently versus placebo at BAY 63–2521 doses of 1 to 5 mg (P < .01). Mean arterial and diastolic pressures were decreased versus placebo at doses of 1 mg (P < .05) and 5 mg (P < .01). Systolic pressure was not significantly affected. BAY 63–2521 was readily absorbed and exhibited dose‐proportional pharmacokinetics. The pharmacodynamic and pharmacokinetic properties of BAY 63–2521 suggest that it can offer a unique mode of action in the treatment of pulmonary hypertension.

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 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.

Riociguat (BAY 63–2521) and Warfarin: A Pharmacodynamic and Pharmacokinetic Interaction Study

Riociguat (BAY 63–2521) and warfarin are likely to be used concomitantly to treat pulmonary hypertension. The aim of this double‐blind, crossover, clinical pharmacological study in 30 healthy volunteers was to investigate potential pharmacodynamic and pharmacokinetic interactions between the 2 drugs. Healthy volunteers took 2.5 mg of oral riociguat or matching placebo 3 times daily for 10 days. A single oral dose of warfarin sodium (25 mg) was given 21 days before the study and on the seventh day of riociguat/placebo treatment. Twenty‐one participants valid for safety analysis reported 89 treatment‐emergent adverse events, all of mild or moderate severity. No serious adverse events occurred. The most frequently reported treatment‐emergent adverse events considered to be drug‐related were dyspepsia, headache, flatulence, nausea, and vomiting. Twenty‐two participants were valid for pharmacodynamic/pharmacokinetic analysis. Riociguat (2.5 mg 3 times daily) had no pharmacodynamic interaction with warfarin. Steady‐state plasma levels of riociguat did not affect prothrombin time, factor VII clotting activity or the pharmacokinetics of warfarin. The single dose of warfarin led to a slight decrease (16%) in maximum concentration of riociguat in plasma, which is not likely to be clinically relevant. Clinical studies will confirm the finding here that combined use of riociguat with warfarin will not require dose adaptation.

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 NOindependent stimulation of sGC and increasing sensitivity of sGC to low levels of NO. Another sGC stimulator, BAY 41-2272, has shown anti-platelet activity in animal models, as have BAY 41-2272 and riociguat in washed human platelets, although bleeding has not been noted as an adverse event (AE) in riociguat clinical studies [1,2]. As riociguat and aspirin are likely to be used together in PH, it was of interest to investigate potential PD and PK interactions.

BAY 58-2667, a soluble guanylate cyclase activator, improves cardiopulmonary haemodynamics in acute decompensated heart failure and has a favourable safety profile

Address: 1HELIOS-Klinikum Erfurt, 99089 Erfurt, Germany, 2Kerckhoff-Klinik Nauheim, 61231 Nauheim, Germany, 3Schuchtermann-Klinik Bad Rothenfelde, 49214 Bad Rothenfelde, Germany, 4St Johannes Hospital Dortmund,44137 Dortmund, Germany, 5Universitat Halle, 06097 Halle, Germany, 6HELIOS-Klinikum Wuppertal, 42283 Wuppertal, Germany, 7Clinical Pharmacology, Bayer HealthCare AG, Pharma Research Centre, 42096 Wuppertal, Germany and 8Global Biostatistics, Bayer HealthCare AG, Pharma Research Centre, 42096 Wuppertal, Germany

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

Cinaciguat is intended for use in patients with acute decompensated heart failure. The drug is eliminated predominantly via the liver and, therefore, the potential impact of hepatic impairment on cinaciguat pharmacokinetics needs to be determined. This nonrandomized, open‐label, observational study investigated the pharmacokinetics of cinaciguat in individuals with mild (Child‐Pugh A; n = 8) or moderate (Child‐Pugh B; n = 8) hepatic impairment and matched healthy volunteers (n = 16). An exploratory analysis of pharmacodynamic parameters was also conducted. Individuals with mild hepatic impairment and their controls received a single (4‐hour) intravenous infusion of 100 μg/h cinaciguat, whereas individuals with moderate hepatic impairment and their controls received 50 μg/h. Cinaciguat was well tolerated and had a favorable safety profile. The most frequent treatment‐emergent adverse events were headache (4 participants) and spontaneous penile erection (2 participants). In individuals with mild hepatic impairment, only minor increases in plasma cinaciguat concentrations and no significant differences in pharmacodynamic parameters were observed, compared with controls. Individuals with moderate hepatic impairment had a substantially higher cinaciguat exposure than controls. This higher exposure was associated with more pronounced vasodilatation. This study demonstrates that in individuals with mild hepatic impairment, individual dose adaptation may not be required.

Assessment of the effects of renal impairment on the pharmacokinetics of the soluble guanylate cyclase activator cinaciguat after a single intravenous dose.

This open‐label, parallel‐group, single‐dose study assessed the safety and pharmacokinetics of cinaciguat, a novel soluble guanylate cyclase activator in clinical development for the treatment of acute decompensated heart failure, in individuals with mild, moderate, or severe renal impairment compared with individuals with normal renal function. Cinaciguat was administered as a 100 μg/h continuous infusion over 4 hours. Plasma concentrations were determined by high‐performance liquid chromatography coupled with mass spectrometry. Renal function had only minor effects on the pharmacokinetics of cinaciguat. The apparent volume of distribution at steady state was slightly increased in individuals with renal impairment. The total body clearance from plasma showed a slight tendency to increase with progression of renal impairment, which can be explained by an increased hematocrit in individuals with renal impairment. No relevant influence was found on the terminal half‐life. The fraction of cinaciguat unbound in plasma was very low (<1%) in all groups. Pharmacokinetic variability tended to be somewhat increased in individuals with renal impairment. Adverse events were mostly mild, and their incidence was similar in all groups. In conclusion, cinaciguat, a promising drug candidate for the treatment of acute decompensated heart failure, will not require dose adjustment based on renal function.

BAY 63–2521, an oral soluble guanylate cyclase stimulator, has a favourable safety profile and decreases peripheral vascular resistance in healthy male volunteers

Background BAY 63–2521 is an oral soluble guanylate cyclase (sGC) stimulator that acts independently of nitric oxide (NO). It targets the reduced form of sGC, and enhances the sensitivity of the enzyme to low levels of bioavailable NO. Preclinical data suggest that BAY 63–2521 has the potential to be effective in the treatment of pulmonary hypertension, with the advantage of having a different mode of action from currently available agents.

BAY 58–2667, a soluble guanylate cyclase activator, has a favourable safety profile and reduces peripheral vascular resistance in healthy male volunteers

Materials and methods This single-site study assessed the safety, tolerability and pharmacokinetics of intravenously administered BAY 58– 2667 in healthy male volunteers. For initial dose-finding, BAY582667 was administered for 2 h at doses of 15 μg/h, 45 μg/h and 100 μg/h (n = 2 per dose group). Safety parameters (adverse events [AEs], electrocardiograms [ECGs] and standard laboratory values), pharmacodynamics (heart rate [HR], mean arterial pressure [MAP], diastolic blood pressure [DBP] and plasma vasoactive hormone levels) and pharmacokinetics were assessed using a single-blinded, randomized, placebo-controlled study design: four doses of BAY 58–2667 (range: 50–200 μg/h) were administered for 2 h or 4 h to six individuals per dose group, with an additional 250 μg/h dose group (n = 5) in the 4-h infusion administration group (placebo groups, n = 7 for the 2-h dose group and n = 10 for the 4h dose group). Results Sixteen AEs occurring in 12 (20%) of 59 subjects receiving BAY 58–2667 were attributed to the study compound. All were of mild intensity, including two cases of mild symptomatic hypotension. There was an increase in the frequency of cardiovascular-related AEs with increasing dose of the study compound. BAY 58–2667 had no clinically relevant effects on ECGs or laboratory values. Pharmacodynamic evaluation showed that BAY582667 increased HR in a dose-dependent manner when infused over 2 h (P = 0.0002) and 4 h (P < 0.0001). In healthy young subjects, the cardiovascular system compensates for changes in blood pressure with changes in HR to keep the blood pressure constant as long as possible. Therefore, HR is considered the most sensitive non-invasive parameter for indirect estimation of the effect of a vasodilating agent on the cardiovascular system. Pharmacodynamic evaluation also showed that BAY 58–2667 dose-dependently decreased MAP (2 h: P = 0.0069; 4 h: P = 0.0008) and DBP (2 h: P = 0.0058; 4 h: P = 0.0004). In terms of vasoactive hormones, BAY 58–2667 dose-dependently increased plasma renin activity (2 h: P = 0.0064; 4 h: P = 0.0212), angiotensin II levels (2 h: P = 0.0042; 4 h: P = 0.0013) and noradrenalin levels (2 h: P < 0.0001; 4 h: P = 0.0002), while having no significant effect on plasma aldosterone levels. Plasma levels of cGMP increased dose-dependently in the 4-h infusion groups (P < 0.0001), but not the 2-h from 3rd International Conference on cGMP Generators, Effectors and Therapeutic Implications Dresden, Germany. 15–17 June 2007

Antiplatelet effects of aspirin are not affected by the soluble guanylate cyclase activator cinaciguat (BAY 58-2667)

IntroductionCinaciguat (BAY 58-2667) is an nitric oxide (NO)-inde-pendent and heme-independent soluble guanylatecyclase (sGC) activator. Cinaciguat preferentially acti-vates sGC in its oxidized or heme-free state, when theenzyme is insensitive to its endogenous ligand NO andexogenous nitrovasodilators [1].Endothelium-derived NO is one of the mechanisms bywhich platelet aggregation and thrombus formation isprevented by the intact blood vessel wall. Pharmacologi-cal stimulation of sGC in platelets correlates with inhibi-tion of aggregation, platelet cGMP increase, prolongationof bleeding time and antithrombotic effects in vitro [2].This protective mechanism may be impaired in vasculardisease and impaired NO availability. Thus, sGC activa-tors may have antithrombotic effects similar to endogen-ous NO. Indeed, cinaciguat potently inhibited plateletaggregation induced by the thromboxane mimic U46619and collagen and prolonged rat-tail bleeding time up to2-fold [3]. Thus, in vitro data suggested that coadminis-tration of cinaciguat and aspirin may increase the antipla-telet effects of aspirin and could result in bleeding.MethodsThis non-randomized, open-label trial was conductedfrom September to November 2001 in a single center inGermany. It was carried out in accordance with theDeclaration of Helsinki and adhered to the InternationalConference of Harmonization good clinical practiceguidelines and the German drug law (AMG). The studyprotocol was approved by the Ethics Committee of theNorth-Rhine Medical Council, Duesseldorf, Germany.The study consisted of a 9-day treatment phase with100 mg oral acetylsalicylicacid (aspirin) once dailyadministered in the morning in the fasting state and,after the last dose of aspirin, four sequential oral dosesof 1.5 mg cinaciguat administered in the fasting state at1-hour intervals. The first dose of cinaciguat was admi-nistered together with the last dose of aspirin. This cina-ciguat dosing schedule was used to mimic a prolongedplasma concentration over time profile.Results12 healthy men (mean age, 32.4 years, range, 23 - 42years) were enrolled and completed the study accordingto protocol.Low-dose aspirin treatment in healthy subjectsresulted in the expected inhibition of platelet aggrega-tion. 4 oral doses of 1.5 mg cinaciguat administered at1-hour intervals did not significantly affect plateletaggregation induced by collagen and the thromboxaneA2 mimetic U 46619 or bleeding time. These results arein line with the findings of a single dose escalationstudy.Plasma pharmacokinetics of cinaciguat following 4oral doses of 1.5 mg cinaciguat administered at 1-hourintervals showed pronounced inter-individual variability.There was no major pharmacokinetic interactiondetected between aspirin and cinaciguat, compared withthe data of a previous study, which applied the samedosing regimen.ConclusionCoadministration of cinaciguat and aspirin did notreveal any pharmacodynamic interaction with respect of