Effects of Tablet Formulation, Food, or Gastric pH on the Bioavailability of Asundexian.

Absolute bioavailability (F) and the impact of gastric pH, tablet formulation, and food on the pharmacokinetics and safety of asundexian, an oral factor XIa inhibitor, was assessed in healthy White men aged 18-45 years in 4 studies. For F, fasted participants received 50 µg of [13 C7 ,15 N]-labeled asundexian intravenously 2 hours after 25 mg of asundexian orally. Tablet formulation (50-mg immediate release [IR], and different amorphous solid dispersion [ASD] IR 25-mg and 50-mg ASD IR tablets) and food effects were explored in 2 studies. Formulation was compared using 50-mg IR versus 25-mg ASD IR and 25-mg ASD IR versus 50-mg ASD IR (fasted); food effect using 25-mg ASD IR and 50-mg ASD IR. Gastric pH modulation was assessed using omeprazole or antacid coadministration with asundexian in the fasted state. Pharmacokinetic parameters included area under the concentration-time curve (AUC; and AUC/dose [D]) and maximum observed concentration (Cmax and Cmax /D) data were evaluable for 59 participants. F was 103.9%. Relative bioavailability with 25-mg ASD IR and 50-mg ASD IR tablets, respectively, was marginally affected by formulation (AUC/D ratios, 94.3% and 95.1%; Cmax /D ratios, 95.5% and 88.7%), food (AUC[/D] ratios, 91.1% and 96.9%; Cmax [/D] ratios: 78.3% and 95.1%), and gastric pH (omeprazole, no effect; antacid, AUC ratio, 89.9% and Cmax ratio, 83.7%). No serious adverse events or deaths occurred; most adverse events were mild or moderate. In summary, oral asundexian was well tolerated and demonstrated complete bioavailability irrespective of tablet formulation, food, or gastric pH.

Pharmacokinetics, Safety, and Tolerability of the α2C -Adrenoreceptor Antagonist BAY 1193397 in Healthy Male Subjects.

The α2C -adrenoreceptor antagonist BAY 1193397 is in development for the oral treatment of diabetic foot ulcers. Safety, tolerability, and pharmacokinetics of BAY 1193397 were investigated in 3 randomized, single-center phase 1 studies in healthy male subjects: a first-in-human study (single oral doses of 0.5-50 mg), a relative bioavailability and food effect study (single doses of 1 and 10 mg), and a multiple-dose escalation study (using 2 and 5 mg twice daily and 10 and 20 mg once daily for 9 consecutive days). BAY 1193397 was rapidly absorbed in the fasted state, peak concentrations were reached between 0.6 and 2 hours. The mean terminal half-life was in the range of 17 to 20 hours. Area under the plasma concentration-time curve and maximum concentration appeared to be dose proportional, with a negligible food effect. There were no high-accumulation effects of BAY 1193397 after repeated dosing. BAY 1193397 was safe and well tolerated. At supratherapeutic plasma concentrations, there were slight transient increases in norepinephrine levels, heart rate, and blood pressure that were more pronounced after a single dose compared to steady state and appeared to be maximum concentration dependent. The results of the presented studies support the conduct of subsequent clinical trials with BAY 1193397 in patients with diabetes and compromised microcirculation.

First evaluation of the safety, pharmacokinetics, and pharmacodynamics of BAY 2433334, a small molecule targeting coagulation factor XIa.

BACKGROUND: Coagulation factor XI (FXI) contributes to the development of thrombosis but appears to play a minor role in hemostasis and is, therefore, an attractive anticoagulant drug target. OBJECTIVES: To evaluate the safety, pharmacokinetic, and pharmacodynamic properties of BAY 2433334, an orally administered small molecule targeting activated FXI (FXIa), in healthy men. PATIENTS/METHODS: This phase 1 study was conducted in two parts. In part 1, 70 volunteers were randomized 4:1 to receive a single oral dose of BAY 2433334 (5-150 mg as oral solution or immediate-release tablets) or placebo. In part 2, 16 volunteers received a single oral dose of five BAY 2433334 5-mg tablets with or without a high-calorie breakfast in a randomized crossover study design. Adverse events, pharmacokinetic parameters, and pharmacodynamic parameters were assessed up to 72 h after drug administration. Volunteers were followed up after 7 to 14 days. RESULTS: BAY 2433334 demonstrated favorable safety and tolerability with a dose-dependent increase in exposure and a terminal half-life of 14.2 to 17.4 h. A high-calorie breakfast reduced mean maximum plasma concentration and exposure by 31% and 12.4%, respectively. AY 2433334 was associated with a dose-dependent inhibition of FXIa activity and an increase in activated partial thromboplastin time. Bleeding times in volunteers who had received BAY 2433334 were similar to those in volunteers who had received placebo. CONCLUSIONS: These data indicate that BAY 2433334 is a promising development candidate for once-daily oral anticoagulation; it is being evaluated in phase 2 dose-finding studies in patients at risk of thrombosis.

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.

BAY 1213790, a fully human IgG1 antibody targeting coagulation factor XIa: First evaluation of safety, pharmacodynamics, and pharmacokinetics.

BACKGROUND: Coagulation factor XI (FXI) contributes to the development of thrombosis but appears to play only a minor role in hemostasis and is therefore an attractive anticoagulant drug target. OBJECTIVES: To evaluate the safety, pharmacodynamic, and pharmacokinetic properties of BAY 1213790, a fully human immunoglobulin (Ig) G1 antibody targeting activated coagulation FXI (FXIa), in healthy men. METHODS: In this phase 1, single-blind, parallel-group, placebo-controlled, dose-escalation study, 83 healthy Caucasian men were randomized 4:1 to receive a single 60-minute intravenous infusion of BAY 1213790 (0.015-10 mg/kg) or placebo. Adverse events, pharmacodynamic parameters (including activated partial thromboplastin time [aPTT]) and pharmacokinetic parameters were determined. Volunteers were followed up for 150 days. RESULTS: BAY 1213790 demonstrated favorable safety and tolerability; there were no observed cases of bleeding or clinically relevant antidrug antibody formation. One volunteer (1.2%) experienced an infusion reaction. Following intravenous administration of BAY 1213790, dose-dependent increases in aPTT (maximal mean increase relative to baseline: 1.85 [conventional method] and 2.17 [kaolin-triggered method]) and rotational thromboelastometry whole blood clotting time were observed, as well as dose-dependent reductions in FXI activity. Bleeding times did not increase following administration of BAY 1213790 and were similar for all dose cohorts, including placebo. Measurable and dose-dependent increases in systemic exposure were detected for all doses of BAY 1213790 of 0.06 mg/kg or higher. CONCLUSIONS: Based on these safety, pharmacodynamic, and pharmacokinetic results, further evaluation of BAY 1213790 in patients with, or at risk of, thrombosis is warranted.

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.

Pharmacokinetics and safety of nifedipine GITS/candesartan fixed-dose combination in subjects with hepatic impairment
.

OBJECTIVE: To investigate the pharmacokinetic (PK) profiles and safety of nifedipine and candesartan after a single oral dose of nifedipine gastrointestinal therapeutic system (GITS) 30 mg/candesartan cilexetil 8 mg (N30/C8 mg) fixed-dose combination (FDC) in adults with mild to moderate hepatic impairment. METHODS: A phase I, single-center, non-randomized, non-controlled, non-blinded, observational study (N = 32). PK profiles for nifedipine and candesartan were assessed in patients with mild (Child-Pugh A; group 1) or moderate (Child-Pugh B; group 2) hepatic impairment and compared with age- and gender-matched healthy controls (groups 3 and 4) following a single dose of N30/C8 FDC. Safety and tolerability were assessed throughout the study. RESULTS: On average, area under the plasma concentration vs. time curves (AUC) for nifedipine increased 93% and 253% in mild and moderate hepatic impairment, while maximum plasma concentrations (Cmax) increased 64% and 171%, respectively. AUC values for candesartan increased 19% and 92%, while Cmax values increased 3% and 11%, respectively. In subjects with or without liver impairment, adverse event rates were similar and consistent with the known side-effect profiles of nifedipine GITS and candesartan as monotherapies. CONCLUSIONS: Careful monitoring, and, if necessary, dose adjustment according to response and tolerability may be required for nifedipine GITS/candesartan FDC in patients with mild and moderate hepatic impairment.
.

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.

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 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.

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.

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.

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.

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.

Acute effects of riociguat in borderline or manifest pulmonary hypertension associated with chronic obstructive pulmonary disease.

Riociguat is the first oral soluble guanylate cyclase stimulator shown to improve pulmonary hemodynamics in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (PH). This pilot study assessed the impact of a single dose of riociguat on hemodynamics, gas exchange, and lung function in patients with PH associated with chronic obstructive pulmonary disease (COPD). Adults with COPD-associated borderline or manifest PH (pulmonary vascular resistance > 270 dyn·s·cm(-5), mean pulmonary artery pressure ≥ 23 mmHg, ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity < 70%, and partial pressure of oxygen and carbon dioxide in arterial blood > 50 and ≤ 55 mmHg, respectively) received riociguat 1 or 2.5 mg during right heart catheterization. Twenty-two patients completed the study (11 men, 11 women, aged 56-82 years; 1-mg group: n = 10 [mean FEV1: 43.1%]; 2.5-mg group: n = 12 [mean FEV1: 41.2%]). Riociguat caused significant improvements (P < 0.01) from baseline in mean pulmonary artery pressure (1 mg: -3.60 mmHg [-11.44%]; 2.5 mg: -4.83 mmHg [-14.76%]) and pulmonary vascular resistance (1 mg: -58.32 dyn·s·cm(-5) [-15.35%]; 2.5 mg: -123.8 dyn·s·cm(-5) [-32.96%]). No relevant changes in lung function or gas exchange were observed. Single doses of riociguat were well tolerated and showed promising hemodynamic effects without untoward effects on gas exchange or lung function in patients with COPD-associated PH. Placebo-controlled studies of chronic treatment with riociguat are warranted.

Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind, placebo-controlled, single-dose study.

BACKGROUND: Deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling results from endothelial dysfunction and may underlie impaired cardiac relaxation in patients with heart failure with preserved left ventricular ejection fraction (HFpEF) and pulmonary hypertension (PH). The acute hemodynamic effects of riociguat, a novel soluble guanylate cyclase stimulator, were characterized in patients with PH and HFpEF. METHODS: Clinically stable patients receiving standard HF therapy with a left ventricular ejection fraction > 50%, mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg, and pulmonary arterial wedge pressure (PAWP) > 15 mm Hg at rest were randomized to single oral doses of placebo or riociguat (0.5, 1, or 2 mg). The primary efficacy variable was the peak decrease in mPAP from baseline up to 6 h. Secondary outcomes included hemodynamic and echocardiographic parameters, safety, and pharmacokinetics. RESULTS: There was no significant change in peak decrease in mPAP with riociguat 2 mg (n = 10) vs placebo (n = 11, P = .6). However, riociguat 2 mg significantly increased stroke volume (+9 mL [95% CI, 0.4-17]; P = .04) and decreased systolic BP (-12 mm Hg [95% CI, -22 to -1]; P = .03) and right ventricular end-diastolic area (-5.6 cm2 [95% CI, -11 to -0.3]; P = .04), without significantly changing heart rate, PAWP, transpulmonary pressure gradient, or pulmonary vascular resistance. Riociguat was well tolerated. CONCLUSIONS: In patients with HFpEF and PH, riociguat was well tolerated, had no significant effect on mPAP, and improved exploratory hemodynamic and echocardiographic parameters. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01172756; URL: www.clinicaltrials.gov.

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.