Stimulation of soluble guanylate cyclase prevents cigarette smoke-induced pulmonary hypertension and emphysema.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide. No therapy stopping progress of the disease is available. OBJECTIVES: To investigate the role of the soluble guanylate cyclase (sGC)-cGMP axis in development of lung emphysema and pulmonary hypertension (PH) and to test whether the sGC-cGMP axis is a treatment target for these conditions. METHODS: Investigations were performed in human lung tissue from patients with COPD, healthy donors, mice, and guinea pigs. Mice were exposed to cigarette smoke (CS) for 6 hours per day, 5 days per week for up to 6 months and treated with BAY 63-2521. Guinea pigs were exposed to CS from six cigarettes per day for 3 months, 5 days per week and treated with BAY 41-2272. Both BAY compounds are sGC stimulators. Gene and protein expression analysis were performed by quantitative real-time polymerase chain reaction and Western blotting. Lung compliance, hemodynamics, right ventricular heart mass alterations, and alveolar and vascular morphometry were performed, as well as inflammatory cell infiltrate assessment. In vitro assays of cell adhesion, proliferation, and apoptosis have been done. MEASUREMENTS AND MAIN RESULTS: The functionally essential sGC ß1-subunit was down-regulated in patients with COPD and in CS-exposed mice. sGC stimulators prevented the development of PH and emphysema in the two different CS-exposed animal models. sGC stimulation prevented peroxynitrite-induced apoptosis of alveolar and endothelial cells, reduced CS-induced inflammatory cell infiltrate in lung parenchyma, and inhibited adhesion of CS-stimulated neutrophils. CONCLUSIONS: The sGC-cGMP axis is perturbed by chronic exposure to CS. Treatment of COPD animal models with sGC stimulators can prevent CS-induced PH and emphysema.

Cinaciguat (BAY 58-2667) improves cardiopulmonary hemodynamics in patients with acute decompensated heart failure.

BACKGROUND: Cinaciguat (BAY 58-2667) is the first of a new class of soluble guanylate cyclase activators in clinical development for acute decompensated heart failure. We aimed to assess the hemodynamic effects, safety, and tolerability of intravenous cinaciguat in patients with acute decompensated heart failure (pulmonary capillary wedge pressure > or =18 mm Hg). METHODS AND RESULTS: After initial dose finding (part A; n=27), cinaciguat was evaluated in the nonrandomized, uncontrolled proof-of-concept part of the study (part B; n=33) using a starting dose of 100 microg/h, which could be titrated depending on hemodynamic response. Patients were categorized as responders if their pulmonary capillary wedge pressure decreased by > or =4 mm Hg compared with baseline. Final doses of cinaciguat after 6 hours of infusion in part B were 50 microg/h (n=2), 200 microg/h (n=12), and 400 microg/h (n=16). Compared with baseline, a 6-hour infusion of cinaciguat led to significant reductions in pulmonary capillary wedge pressure (-7.9 mm Hg), mean right atrial pressure (-2.9 mm Hg), mean pulmonary artery pressure (-6.5 mm Hg), pulmonary vascular resistance (-43.4 dynes . s . cm(-5)), and systemic vascular resistance (-597 dynes . s . cm(-5)), while increasing heart rate by 4.4 bpm and cardiac output by 1.68 L/min. The responder rate was 53% after 2 hours, 83% after 4 hours, and 90% after 6 hours. Cinaciguat was well tolerated, with 13 of 60 patients reporting 14 drug-related treatment-emergent adverse events of mild to moderate intensity, most commonly hypotension. CONCLUSIONS: Cinaciguat has potent preload- and afterload-reducing effects, increasing cardiac output. Further investigation of cinaciguat for acute decompensated heart failure is warranted.

Pharmacokinetic interaction of riociguat and antiretroviral combination regimens in HIV-1-infected adults.

Riociguat, a first-in-class soluble guanylate cyclase stimulator, is approved for the treatment of pulmonary arterial hypertension (PAH), a serious potential complication of human immunodeficiency virus (HIV) infection. This open-label study investigated the pharmacokinetic drug-drug interaction potential of antiretroviral therapies on riociguat exposure in HIV-infected adults. HIV-infected adults without PAH on stable antiretroviral regimens (efavirenz/emtricitabine/tenofovir disoproxil, emtricitabine/rilpivirine/tenofovir disoproxil, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil, abacavir/dolutegravir/lamivudine, or a ritonavir-boosted triple regimen) for ≥ 6 weeks received a single riociguat dose (0.5 mg). Riociguat pharmacokinetics and safety were assessed; pharmacokinetics was compared with historical healthy volunteer data. Of 41 participants treated (n = 8 in each arm, except n = 9 in the ritonavir-boosted triple regimen arm), 40 were included in the pharmacokinetic analyses. Riociguat median tmax was 1.00-1.27 h, with comparable maximum concentration (Cmax) across the five background antiretroviral groups. Riociguat exposure was highest with abacavir/dolutegravir/lamivudine, followed by elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil > emtricitabine/rilpivirine/tenofovir disoproxil > ritonavir-boosted triple regimen > efavirenz/emtricitabine/tenofovir disoproxil; riociguat area under the plasma concentration versus time curve (AUC) was approximately threefold higher with abacavir/dolutegravir/lamivudine than efavirenz/emtricitabine/tenofovir disoproxil. Compared with historical data, riociguat exposure in HIV-infected adults was similar when co-administered with efavirenz/emtricitabine/tenofovir disoproxil, slightly increased when administered with ritonavir-boosted triple regimen and increased by approximately threefold when administered with abacavir/dolutegravir/lamivudine. Riociguat was well tolerated, with no new safety findings. Riociguat was well tolerated in adults with HIV on stable background antiretroviral therapy although an apparent increase in AUC of riociguat was observed in patients receiving abacavir/dolutegravir/lamivudine. Patients should be monitored closely during riociguat initiation and dose adjustment for signs and symptoms of hypotension.

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.

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.

Clinical Pharmacokinetic and Pharmacodynamic Profile of Riociguat.

Oral riociguat is a soluble guanylate cyclase (sGC) stimulator that targets the nitric oxide (NO)-sGC-cyclic guanosine monophosphate pathway with a dual mode of action: directly by stimulating sGC, and indirectly by increasing the sensitivity of sGC to NO. It is rapidly absorbed, displays almost complete bioavailability (94.3%), and can be taken with or without food and as crushed or whole tablets. Riociguat exposure shows pronounced interindividual (60%) and low intraindividual (30%) variability in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH), and is therefore administered using an individual dose-adjustment scheme at treatment initiation. The half-life of riociguat is approximately 12 h in patients and approximately 7 h in healthy individuals. Riociguat and its metabolites are excreted via both renal (33-45%) and biliary routes (48-59%), and dose adjustment should be performed with particular care in patients with moderate hepatic impairment or mild to severe renal impairment (no data exist for patients with severe hepatic impairment). The pharmacodynamic effects of riociguat reflect the action of a vasodilatory agent, and the hemodynamic response to riociguat correlated with riociguat exposure in patients with PAH or CTEPH in phase III population pharmacokinetic/pharmacodynamic analyses. Riociguat has a low risk of clinically relevant drug interactions due to its clearance by multiple cytochrome P450 (CYP) enzymes and its lack of effect on major CYP isoforms and transporter proteins at therapeutic levels. Riociguat has been approved for the treatment of PAH and CTEPH that is inoperable or persistent/recurrent after surgical treatment.

Individual dose adjustment of riociguat in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Riociguat is a soluble guanylate cyclase stimulator that has been approved for the treatment of pulmonary arterial hypertension and inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension following pulmonary endarterectomy. Riociguat is administered using an 8-week individual dose-adjustment scheme whereby a patient initially receives riociguat 1.0 mg three times daily (tid), and the dose is then increased every 2 weeks in the absence of hypotension, indicated by systolic blood pressure measurements and symptoms, up to a maximum dose of 2.5 mg tid. The established riociguat dose-adjustment scheme allows the dose of riociguat to be individually optimized in terms of tolerability and efficacy. The majority of patients in the phase III clinical trials and their long-term extension phases achieved the maximum riociguat dose, whereas some patients remained on lower doses. There is evidence that these patients may experience benefits at riociguat doses lower than 2.5 mg tid, with improvement in exercise capacity being observed after only 2-4 weeks of treatment in the phase III studies and in the exploratory 1.5 mg-maximum patient group of PATENT-1. This review aims to provide an overview of the rationale behind the riociguat dose-adjustment scheme and examine its application to both clinical trials and real-life clinical practice.

Effects of age and sex on the pharmacokinetics of the soluble guanylate cyclase stimulator riociguat (BAY 63-2521).

Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). This randomized, double-blind, placebo-controlled study investigated the pharmacokinetics of riociguat and its metabolite M1 in young (18-45 years) and elderly (64.5-80 years) healthy volunteers of both sexes to assist planning of the dose regimens for clinical trials. The data were also used to draw comparisons with the effects of age and sex on riociguat pharmacokinetics in patients with PAH and CTEPH from the riociguat phase 3 trials, PATENT and CHEST. Volunteers received an oral dose of either riociguat 2.5 mg or placebo, and the concentrations of riociguat and M1 in blood and urine samples were determined using mass spectrometry. In elderly healthy volunteers, overall riociguat and M1 exposure tended to be higher than in young healthy volunteers (P > 0.05), partly because of reduced renal clearance (approximately 28% reduction) and differences in body weight. Although the mean maximum concentrations of riociguat and M1 were significantly higher in women than in men (35% and 50% higher, respectively), total exposure was similar. Despite differences in riociguat and M1 pharmacokinetics, riociguat was well tolerated with a comparable safety profile across all subgroups, suggesting that differences in drug exposure due to age or sex were not sufficient to warrant a dose adjustment in clinical trials. Furthermore, similar pharmacokinetics were observed in patients with PAH and CTEPH. However, particular care should be exercised during individual dose titration of riociguat in elderly patients.

Population pharmacokinetics of single-dose riociguat in patients with renal or hepatic impairment.

This population pharmacokinetics (PK) analysis characterized the PK of the oral soluble guanylate cyclase stimulator riociguat in patients with renal or hepatic impairment and determined whether smoking affects riociguat dosing. Two phase 1 studies were performed in patients with renal impairment (n = 72, of whom 11 were smokers), and two were performed in those with hepatic impairment (n = 64, of whom 12 were smokers). Plasma and urine samples were collected after a single oral dose of riociguat 1.0 or 0.5 mg. Nonlinear mixed-effects modeling was used to develop a combined, two-compartment population PK model for riociguat and its main metabolite, M1. Riociguat and M1 clearance was split into renal and nonrenal parts; the nonrenal part for riociguat was divided into metabolism to M1 and a metabolic (nonrenal) part. Total clearance of riociguat was 1.912 L/h. The main route of riociguat clearance is metabolism to M1 (1.2 L/h). In this model, hepatic function biomarkers or Child-Pugh classification had no significant effect on riociguat or M1 clearance. Nonrenal (nonmetabolism) riociguat clearance was similar in all groups. Renal clearance (0.242 L/h) contributed less to riociguat total clearance, mainly determined by glomerular filtration (0.174 L/h). Renal impairment reduced riociguat and M1 clearance. Hepatic or renal impairment had limited effects on total exposure to riociguat. However, individual dose adjustment of riociguat should be administered with particular care in patients with moderate hepatic or renal impairment. Riociguat is not recommended in severe hepatic or renal impairment. Smoking reduced riociguat exposure by significantly increasing metabolism to M1.

Population pharmacokinetics and the pharmacokinetic/pharmacodynamic relationship of riociguat in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension.

This analysis aimed to characterize the pharmacokinetics (PK) and PK/pharmacodynamic (PK/PD) relationship of riociguat and its metabolite M1 in patients with chronic thromboembolic pulmonary hypertension (CTEPH) or pulmonary arterial hypertension (PAH). Blood samples were collected in two phase 3 studies-PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1; 12 weeks; PAH) and CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1; 16 weeks; CTEPH)-and long-term extensions. Patients were initially randomized to receive placebo or riociguat, and they received riociguat in the extensions. Nonlinear mixed-effects modeling was used to develop a population PK model describing riociguat PK. PK/PD relationships were investigated by comparing derived PK parameters with changes in PD parameters. Covariate analyses included smoking status, bosentan comedication, bilirubin levels, and baseline creatinine clearance. The PK of riociguat/M1 was described by a one-compartment model. Mean population estimates for riociguat absorption rate constant, clearance, and volume of distribution were 2.17/h, 1.81 L/h, and 32.3 L, respectively; for M1 they were 0.258/h, 3.16 L/h, and 124 L. Interindividual variability was moderate for riociguat and moderate to high for M1. There was no evidence of time- or dose-dependent changes in riociguat/M1 PK. Riociguat clearance was higher in smokers (120% increase) and bosentan-treated patients (36% increase) than in nonsmokers and those not receiving bosentan. There was an inverse correlation between bilirubin and riociguat clearance. In PK/PD analyses, 6-minute walk distance was related to hemodynamic parameters, particularly pulmonary vascular resistance. Riociguat PK were described by a one-compartment model. Effects of covariates on riociguat and M1 PK were established, and a PK/PD relationship was demonstrated. (ClinicalTrials.gov identifiers: PATENT-1, NCT00810693; PATENT-2, NCT00863681; CHEST-1, NCT00855465; CHEST-2, NCT00910429.).

Absorption of riociguat (BAY 63-2521): bioavailability, food effects, and dose proportionality.

Riociguat (BAY 63-2521) is the first member of a novel class of compounds, the soluble guanylate cyclase (sGC) stimulators. Riociguat has a dual mode of action: it sensitizes sGC to endogenous nitric oxide (NO) and stimulates sGC independent of NO availability. To characterize the biopharmaceutical properties of riociguat, including absolute bioavailability, food interactions, and dose proportionality, riociguat (intravenous/oral) was administered to healthy male subjects in 3 open-label, randomized, crossover studies: absolute bioavailability (1 mg; [Formula: see text]), food effect (2.5 mg; [Formula: see text]), and dose proportionality (0.5-2.5 mg; [Formula: see text]). Absolute bioavailability was 94% (95% confidence interval [CI], 83%-107%). Riociguat absorption was delayed by a high-fat breakfast with little effect on the extent of absorption (area under the concentration-time curve [AUC]fed∶AUCfasted, 88% [90% CI, 82%-95%]). Exposure to riociguat was dose proportional over all doses (common slope of AUC, 1.09 [90% CI, 1.04-1.14]; maximum concentration, 0.98 [90% CI, 0.93-1.04]). Intraindividual variability was low; interindividual variability was moderate to high. Riociguat was well tolerated, and adverse events were consistent with the mode of action. In conclusion, riociguat shows complete oral absorption, no clinically relevant food effects, and a dose-proportional increase in systemic exposure (0.5-2.5 mg). These data support the suitability of the individualized dose adjustment scheme employed in the phase 3 clinical studies.

Assessment of the effects of renal impairment and smoking on the pharmacokinetics of a single oral dose of the soluble guanylate cyclase stimulator riociguat (BAY 63-2521).

Renal impairment is a common comborbidity in patients with pulmonary hypertension. The breakdown of riociguat, an oral soluble guanylate cyclase stimulator used to treat pulmonary hypertension, may be affected by smoking because polycyclic aromatic hydrocarbons in tobacco smoke induce expression of one of the metabolizing enzymes, CYP1A1. Two nonrandomized, nonblinded studies were therefore performed to investigate the pharmacokinetics and safety of a single oral dose of riociguat 1.0 mg in individuals with mild, moderate, or severe renal impairment compared with age-, weight-, and sex-matched healthy controls, including either smokers and nonsmokers (study I) or nonsmokers alone (study II). Pharmacokinetic analyses focused on the integrated per-protocol data set of both studies (N = 63). In patients with renal impairment, the renal clearance of riociguat was reduced and its terminal half-life prolonged compared with those in healthy controls. There was a monotonic relationship between creatinine clearance on treatment day and riociguat renal clearance (R (2) = 0.62). However, increased riociguat exposure with decreasing renal function was not strictly proportional. Riociguat exposure appeared to be greater in nonsmokers than in the combined population of smokers and nonsmokers, irrespective of renal function. Adverse events were mild to moderate and in line with the mode of action of riociguat. No serious adverse events occurred. In conclusion, renal impairment was associated with reduced riociguat clearance compared with that in controls; however, riociguat exposure in patients with renal impairment was highly variable, and ranges overlapped with those observed in healthy controls.

Riociguat (BAY 63-2521) and aspirin: a randomized, pharmacodynamic, and pharmacokinetic interaction study.

In preclinical studies, drugs that increase cyclic guanosine monophosphate levels have been shown to influence platelet function/aggregation; however, the effect of riociguat on human platelets is unclear. Aspirin, a platelet inhibitor, is likely to be given concomitantly in patients receiving riociguat. It is therefore important to establish clinically whether (1) riociguat affects platelet function and (2) aspirin and riociguat interact. This randomized, open-label, crossover study investigated potential pharmacodynamic and pharmacokinetic interactions between these drugs in healthy male volunteers (N = 18). There were 3 treatment regimens: a single morning dose of riociguat 2.5 mg, aspirin 500 mg on 2 consecutive mornings, and both treatments together, with riociguat given on the second morning. Fifteen participants were available for pharmacodynamic/pharmacokinetic analysis. There was no effect of riociguat alone on bleeding time, platelet aggregation, and serum thromboxane B2 levels. The effects of aspirin on these parameters were not influenced by concomitant administration of riociguat. The pharmacokinetic profile of riociguat showed interindividual variability, which was independent of aspirin coadministration. Six of 17 participants available for safety evaluation reported at least 1 treatment-emergent adverse event. All adverse events were of mild severity, apart from 1 report of moderate headache. No serious adverse events occurred. In conclusion, riociguat demonstrated no clinically relevant pharmacodynamic or pharmacokinetic interactions with aspirin at the doses used in this study in healthy men; coadministration of riociguat and aspirin should therefore not require any dose adjustment for either drug.

Assessment of the effects of hepatic impairment and smoking on the pharmacokinetics of a single oral dose of the soluble guanylate cyclase stimulator riociguat (BAY 63-2521).

Riociguat, a soluble guanylate cyclase stimulator developed for the treatment of pulmonary hypertension, is metabolized in part by the liver. Expression of one of the metabolizing enzymes, CYP1A1, is induced by aromatic hydrocarbons in tobacco smoke. Two nonrandomized, nonblinded studies were conducted to investigate the pharmacokinetics of riociguat in individuals with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment associated with liver cirrhosis compared with that in age-, weight-, and sex-matched healthy controls: study 1 included smokers and nonsmokers, and study 2 included nonsmokers only. Data from these studies were integrated for analysis. All participants (N = 64) received a single oral dose of riociguat 1.0 mg. Riociguat exposure was significantly higher in individuals with Child-Pugh B hepatic impairment than in healthy controls (ratio: 153% [90% confidence interval: 103%-228%]) but was similar in those with Child-Pugh A hepatic impairment and controls. The half-life of the riociguat metabolite M1 was prolonged in patients with Child-Pugh B or A hepatic impairment compared with that in controls by approximately 43% and 24%, respectively. Impaired hepatic function was associated with higher riociguat exposure in nonsmokers compared with the population of smokers and nonsmokers combined. Riociguat's safety profile was similar in individuals with impaired or normal liver function. In conclusion, moderate hepatic impairment was associated with increased riociguat exposure compared with that in controls, probably as a result of reduced clearance of the metabolite M1. This suggests that dose titration of riociguat should be administered with particular care in patients with moderate hepatic impairment.

Bioavailability, pharmacokinetics, and safety of riociguat given as an oral suspension or crushed tablet with and without food.

Riociguat is approved for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Some patients have difficulty swallowing tablets; therefore, 2 randomized, nonblinded, crossover studies compared the relative bioavailability of riociguat oral suspensions and immediate-release (IR) tablet and of crushed-tablet preparations versus whole IR tablet. In study 1, 30 healthy subjects received 5 single riociguat doses: 0.3 and 2.4 mg (0.15 mg/mL suspensions), 0.15 mg (0.03 mg/mL), and 1.0 mg (whole IR tablet) under fasted conditions and 2.4 mg (0.15 mg/mL) after a high-fat, high-calorie American-style breakfast. In study 2, 25 healthy men received 4 single 2.5-mg doses: whole IR tablet and crushed IR tablet suspended in applesauce and water, respectively, under fasted conditions, and whole IR tablet after a continental breakfast. In study 1, dose-normalized pharmacokinetics of riociguat oral suspensions and 1.0-mg whole IR tablet were similar in fasted conditions; 90% confidence intervals for riociguat area under the curve (AUC) to dose and mean maximum concentration (C max) to dose were within bioequivalence criteria. After food, dose-normalized AUC and C max decreased by 15% and 38%, respectively. In study 2, riociguat exposure was similar for all preparations; AUC ratios for crushed-IR-tablet preparations to whole IR tablet were within bioequivalence criteria. The C max increased by 17% for crushed IR tablet in water versus whole IR tablet. Food intake decreased C max of the whole tablet by 16%, with unaltered AUC versus fasted conditions. Riociguat bioavailability was similar between the oral suspensions and the whole IR tablet; exposure was similar between whole IR tablet and crushed-IR-tablet preparations. Minor food effects were observed. Results suggest that riociguat formulations are interchangeable.

Effects of omeprazole and aluminum hydroxide/magnesium hydroxide on riociguat absorption.

Riociguat, a soluble guanylate cyclase stimulator, is a novel therapy for the treatment of pulmonary hypertension. Riociguat bioavailability is reduced in neutral versus acidic conditions and therefore may be affected by concomitant use of medications that increase gastric pH. The effect of coadministration of the proton pump inhibitor omeprazole or the antacid AlOH/MgOH on the pharmacokinetics, safety, and tolerability of riociguat 2.5 mg was characterized in two open-label, randomized, crossover studies in healthy males. In study 1, subjects pretreated for 4 days with omeprazole 40 mg received cotreatment with omeprazole plus riociguat or riociguat alone (no pretreatment) on day 5 (n = 12). In study 2, subjects received cotreatment with 10 mL AlOH/MgOH plus riociguat or riociguat alone (n = 12). Pre- and cotreatment with omeprazole decreased riociguat bioavailability (mean decreases in area under the plasma concentration-time curve [AUC] and maximum concentration in plasma [C max] were 26% and 35%, respectively). Cotreatment with AlOH/MgOH resulted in greater decreases in riociguat bioavailability (mean decreases in AUC and C max were 34% and 56%, respectively). In both studies, most adverse events (AEs) were of mild intensity, and no serious AEs were reported. No additional safety signals were identified. Treatment with riociguat, with or without omeprazole or AlOH/MgOH, was well tolerated, with a good safety profile. Owing to the resulting increase of gastric pH, riociguat bioavailability is reduced by coadministration with AlOH/MgOH and, to a lesser extent, by coadministration with omeprazole. Thus, antacids should not be administered within an hour of receiving riociguat, but no dose adjustment is required for coadministration of proton pump inhibitors.

Pharmacokinetic interaction study between riociguat and the combined oral contraceptives levonorgestrel and ethinylestradiol in healthy postmenopausal women.

Female patients requiring treatment for pulmonary arterial hypertension (PAH) are advised to avoid pregnancy because of the high associated mortality rate. Oral contraception is one of the main methods of preventing pregnancy in this context, mandating pharmacokinetic and safety studies for new agents in this setting. Riociguat is a soluble guanylate cyclase stimulator approved for treatment of PAH and inoperable and persistent or recurrent chronic thromboembolic pulmonary hypertension. This single-center, randomized, nonblinded study involving healthy postmenopausal women investigated the effect of riociguat on plasma concentrations of levonorgestrel (0.15 mg) and ethinylestradiol (0.03 mg) in a combined oral contraceptive. Treatment A was a single oral tablet of levonorgestrel-ethinylestradiol. In treatment B, subjects received 2.5 mg riociguat 3 times daily for 12 days. On the eighth day, they also received a single oral tablet of levonorgestrel-ethinylestradiol. Subjects received both regimens in a crossover design. There was no change in area under the plasma concentration-time curves of levonorgestrel or ethinylestradiol or maximum concentration in plasma (C max) of levonorgestrel during combined administration versus levonorgestrel-ethinylestradiol alone. A 20% increase in the C max of ethinylestradiol was noted during coadministration; this is not anticipated to adversely impact the contraceptive efficacy or to require any dose adjustment for ethinylestradiol. Plasma concentrations and exposures of riociguat were within the expected range and were not influenced by coadministration with levonorgestrel-ethinylestradiol. Combined treatment was safe and well tolerated. In conclusion, riociguat did not change the exposure to levonorgestrel or ethinylestradiol relative to oral contraceptive administered alone.

Pharmacokinetics of the Soluble Guanylate Cyclase Stimulator Riociguat in Healthy Young Chinese Male Non-Smokers and Smokers: Results of a Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the pharmacokinetics, safety, and tolerability of riociguat after single and multiple oral doses of 1 or 2 mg three times daily (tid), and to determine the effect of smoking on riociguat pharmacokinetics in Chinese men. METHODS: In a randomized, double-blind, placebo-controlled, single-center study stratified for smokers and non-smokers, healthy Chinese men aged 18-45 years received two riociguat doses: Dose Step 1 (1 mg) then Dose Step 2 (2 mg) conducted after the safety and tolerability at Dose Step 1 was confirmed. For each step, 12 subjects received riociguat and six received placebo. A single dose was given on Day 1, followed by a 48-h pharmacokinetic profile. Multiple-dose treatment tid was then given for 6 days (Days 3-8), with a last single dose on Day 9, followed by a 72-h pharmacokinetic profile. Primary outcomes were pharmacokinetic parameters for riociguat after single and multiple dosing. RESULTS: Thirty-six subjects (18 smokers; 18 non-smokers) were randomized and provided valid pharmacokinetic data. Riociguat and its pharmacologically active metabolite M1 (BAY 60-4552) showed nearly dose-proportional pharmacokinetics. Accumulation was minimal in smokers and approximately two-fold in non-smokers. Exposure for riociguat was decreased by ≥60% in smokers. No serious or significant adverse events occurred during the study. CONCLUSIONS: Riociguat pharmacokinetics showed dose proportionality in healthy Chinese men, as previously demonstrated in healthy white male individuals. Exposure to riociguat was substantially decreased in smokers compared with non-smokers. Riociguat was well tolerated in Chinese men.

Pharmacokinetic interaction of riociguat with ketoconazole, clarithromycin, and midazolam.

Riociguat is a soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension that is principally metabolized via the cytochrome P450 (CYP) pathway. Three studies in healthy males investigated potential pharmacokinetic interactions between riociguat and CYP inhibitors (ketoconazole, clarithromycin, and midazolam). In two studies, subjects were pretreated with either once-daily ketoconazole 400 mg or twice-daily clarithromycin 500 mg for 4 days before cotreatment with either riociguat 0.5 mg ± ketoconazole 400 mg or riociguat 1.0 mg ± clarithromycin 500 mg. In the third study, subjects received riociguat 2.5 mg 3 times daily (tid) for 3 days, followed by cotreatment with riociguat 2.5 mg tid ± midazolam 7.5 mg. Pharmacokinetic parameters, the effect of smoking on riociguat pharmacokinetics, safety, and tolerability were assessed. Pre- and cotreatment with ketoconazole and clarithromycin led to increased riociguat exposure. Pre- and cotreatment with riociguat had no significant effect on midazolam plasma concentrations. In all studies, the bioavailability of riociguat was reduced in smokers because its clearance to the metabolite M1 increased. Riociguat ± ketoconazole, clarithromycin, or midazolam was generally well tolerated. The most common treatment-emergent adverse events (TEAEs) across all studies were headache and dyspepsia. One serious TEAE was reported in the midazolam study. Owing to the potential for hypotension, concomitant use of riociguat with multipathway inhibitors, such as ketoconazole, should be approached with caution. Coadministration of riociguat with strong CYP3A4 inhibitors, for example, clarithromycin, does not require additional dose adjustment. No significant drug-drug interaction was revealed between riociguat and midazolam.

Evaluation of the pharmacoDYNAMIC effects of riociguat in subjects with pulmonary hypertension and heart failure with preserved ejection fraction : Study protocol for a randomized controlled trial.

BACKGROUND: The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFPEF) resulting in substantial morbidity and mortality. So far, neither established heart failure therapies nor pulmonary vasodilators have proven to be effective for this condition. Riociguat (Adempas®, BAY 63-2521), a stimulator of soluble guanylate cyclase, is a novel pulmonary and systemic vasodilator that has been approved for the treatment of precapillary forms of PH. With regard to postcapillary PH, the DILATE-1 study was a multicenter, double-blind, randomized, placebo-controlled single-dose study in subjects with PH associated with HFPEF. Although there was no significant change in the primary outcome measure, peak decrease in mean pulmonary artery pressure with riociguat versus placebo, riociguat significantly increased stroke volume without changing heart rate, pulmonary artery wedge pressure, transpulmonary pressure gradient or pulmonary vascular resistance. The present study is designed to test the efficacy of long-term treatment with riociguat in patients with PH associated with HFPEF. METHODS/STUDY DESIGN: The DYNAMIC study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical phase IIb trial evaluating the efficacy, safety and kinetics of riociguat in PH-HFPEF patients. The drug will be given over 26 weeks to evaluate the effects of riociguat versus placebo. The primary efficacy variable will be the change from baseline in cardiac output at rest, measured by right heart catheter after 26 weeks of study drug treatment. Additional efficacy variables will be changes from baseline in further hemodynamic parameters, changes in left and right atrial area, right ventricular volume, as well as right ventricular ejection fraction measured by cardiac magnetic resonance imaging, and changes from baseline in World Health Organization (WHO) class and N­terminal prohormone B­type natriuretic peptide (NT-proBNP). The trial was registered on 25 August 2014 (EudraCT Number: 2014-003055-60; www.clinicaltrialsregister.eu ).