Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Sigrun Unger is active.

Publication


Featured researches published by Sigrun Unger.


European Respiratory Journal | 2009

First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension.

F. Grimminger; Gerrit Weimann; Reiner Frey; Robert Voswinckel; Melanie Thamm; D. Bölkow; Norbert Weissmann; W. Mück; Sigrun Unger; G. Wensing; Ralph T. Schermuly; Hossein-Ardeschir Ghofrani

Pulmonary hypertension (PH) is associated with impaired production of the vasodilator nitric oxide (NO). Riociguat (BAY 63-2521; Bayer Healthcare AG, Wuppertal, Germany) acts directly on soluble guanylate cyclase, stimulating the enzyme and increasing sensitivity to low NO levels. The present study evaluates riociguat safety, tolerability and efficacy in patients with moderate-to-severe PH (pulmonary arterial hypertension, distal chronic thromboembolic PH or PH with mild to moderate interstitial lung disease). The optimal tolerated dose was identified by incremental dosing in four patients with PH; pharmacodynamic and pharmacokinetic parameters were assessed following single-dose administration (2.5 mg or 1 mg) in 10 and five patients with PH, respectively. All subjects (n = 19) were analysed for safety and tolerability. Riociguat had a favourable safety profile at single doses ≤2.5 mg. It significantly improved pulmonary haemodynamic parameters and cardiac index in patients with PH in a dose-dependent manner, to a greater extent than inhaled NO. Although riociguat also had significant systemic effects and showed no pulmonary selectivity, mean systolic blood pressure remained >110 mmHg. The present report is the first to describe the use of riociguat in patients with pulmonary hypertension. The drug was well-tolerated and superior to nitric oxide in efficacy and duration. Riociguat, therefore, has potential as a novel therapy for pulmonary hypertension and warrants further investigation.


Chest | 2014

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

Diana Bonderman; Ingrid Pretsch; Regina Steringer-Mascherbauer; Pavel Jansa; Stephan Rosenkranz; Caroline Tufaro; Andja Bojic; Carolyn S.P. Lam; Reiner Frey; Michael Ochan Kilama; Sigrun Unger; Lothar Roessig; Irene M. Lang

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


Pulmonary circulation | 2015

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

Hossein Ardeschir Ghofrani; Gerd Staehler; Michael Halank; Veselin Mitrovic; Sigrun Unger; Wolfgang Mueck; Reiner Frey; Friedrich Grimminger; Ralph T. Schermuly; Juergen Behr

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.


BMC Clinical Pharmacology | 2013

Pharmacokinetics of the soluble guanylate cyclase stimulator riociguat in individuals with renal impairment

Reiner Frey; Corina Becker; Sigrun Unger; Anja Schmidt; Georg Wensing; Wolfgang Mueck

Riociguat is the first oral soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension. This pooled analysis of two non-randomized, non-blinded, observational studies evaluated the pharmacokinetics of riociguat and its metabolite M1 (BAY 60-4552) in individuals with and without renal impairment. Participants were assigned to 1 of 4 groups according to their creatinine clearance (CLCR): group 1, CLCR > 80 mL/min; group 2, CLCR 50–80 mL/min; group 3, CLCR 30–49 mL/min; group 4, CLCR < 30 mL/min. In the first study, group 4 received 0.5 mg riociguat; all other participants in both studies received 1 mg (single tablet doses). Pharmacokinetics were assessed using dense sampling. 63 participants (40 m, 23 f; age 36–78 years) completed the study. Riociguat was rapidly absorbed; median time to reach maximum concentration in plasma was 1 h in all 4 groups. Mean half-life of total riociguat was longer in groups 2–4 (9.5–11.4 h) than in group 1 (6.2 h), and renal clearance decreased with decreasing renal function. Exposure to total riociguat (mean area under the concentration–time curve/dose per kg body weight), was up to ∼100% higher in groups 2–4 than in group 1. However, exposure was highly variable in groups 2–4. Results for unbound riociguat and unbound M1 were similar to those for total riociguat and total M1. No serious or severe adverse events occurred. No change in safety or tolerability was observed with decreasing CLCR. Thus, the safety profile of riociguat in individuals with renal impairment was similar to that in healthy controls. Riociguat exposure was greater in individuals with renal impairment than in healthy controls, and was highly variable.


Pulmonary circulation | 2016

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):

Reiner Frey; Corina Becker; Sigrun Unger; Anja Schmidt; Georg Wensing; Wolfgang Mück

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 non-∗∗∗randomized, 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. Riociguats 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.


BMC Clinical Pharmacology | 2013

Pharmacokinetic interaction of ketoconazole, clarithromycin, and midazolam with riociguat

Corina Becker; Reiner Frey; Sigrun Unger; Dirk Thomas; Michael Reber; Gerrit Weimann; Hartmut Dietrich; Erich R. Arens; Wolfgang Mueck

Background Riociguat, an oral soluble guanylate cyclase stimulator, is under investigation for pulmonary hypertension treatment. Cytochrome P450 (CYP)-mediated oxidative metabolism is one of the major riociguat clearance pathways. The pharmacokinetic interactions between riociguat and ketoconazole (multi-pathway CYP and P-glycoprotein/ breast cancer resistance protein [P-gp/BCRP] inhibitor), clarithromycin (CYP3A4 inhibitor), and midazolam (CYP3A4 substrate) were investigated.


Pulmonary circulation | 2016

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

Soundos Saleh; Reiner Frey; Corina Becker; Sigrun Unger; Georg Wensing; Wolfgang Mück

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 (Cmax) to dose were within bioequivalence criteria. After food, dose-normalized AUC and Cmax 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 Cmax increased by 17% for crushed IR tablet in water versus whole IR tablet. Food intake decreased Cmax 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.


Pulmonary circulation | 2016

Pharmacokinetic interaction of riociguat with ketoconazole, clarithromycin, and midazolam

Corina Becker; Reiner Frey; Sigrun Unger; Dirk Thomas; Michael Reber; Gerrit Weimann; Hartmut Dietrich; Erich R. Arens; Wolfgang Mück

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.


Pulmonary circulation | 2016

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

Corina Becker; Reiner Frey; Christiane Hesse; Sigrun Unger; Michael Reber; Wolfgang Mück

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; n = 22), food effect (2.5 mg; n = 23), and dose proportionality (0.5–2.5 mg; n = 24). 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.


Pulmonary circulation | 2016

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

Reiner Frey; Michael Reber; Jörn Krätzschmar; Sigrun Unger; Wolfgang Mück; Georg Wensing

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.

Collaboration


Dive into the Sigrun Unger's collaboration.

Top Co-Authors

Avatar

Reiner Frey

Bayer HealthCare Pharmaceuticals

View shared research outputs
Top Co-Authors

Avatar

Corina Becker

Bayer HealthCare Pharmaceuticals

View shared research outputs
Top Co-Authors

Avatar

Wolfgang Mück

Bayer HealthCare Pharmaceuticals

View shared research outputs
Top Co-Authors

Avatar

Michael Reber

Bayer HealthCare Pharmaceuticals

View shared research outputs
Top Co-Authors

Avatar

Wolfgang Mueck

Bayer HealthCare Pharmaceuticals

View shared research outputs
Top Co-Authors

Avatar

Georg Wensing

Bayer HealthCare Pharmaceuticals

View shared research outputs
Top Co-Authors

Avatar

Gerrit Weimann

Bayer HealthCare Pharmaceuticals

View shared research outputs
Top Co-Authors

Avatar

Christiane Hesse

Bayer HealthCare Pharmaceuticals

View shared research outputs
Top Co-Authors

Avatar

Dirk Thomas

Bayer HealthCare Pharmaceuticals

View shared research outputs
Top Co-Authors

Avatar

Erich R. Arens

Bayer HealthCare Pharmaceuticals

View shared research outputs
Researchain Logo
Decentralizing Knowledge