Study on the Safety of BAY 63-2521, How it is Tolerated and the Way the Body Absorbs, Distributes and Gets Rid of the Study Drug Given as a Single Oral Dose of 1 mg Tablet in Participants With Impaired Liver Function and Healthy Participants Matched for Age-, Gender-, and Weight

Study Overview
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Brief Summary
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BAY 63-2521 is intended to be used for a disease that affects the blood flow through the lungs. Renal impairment is a common condition in patients with this disease. The goal of the study is to learn more about the safety of BAY 63-2521, how it is tolerated and the way the body absorbs, distributes and gets rid of the study dug given as a single oral dose of 1 mg tablet in participants with renal impairment and healthy participants matched for age-, gender-, and weight

Official Title
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Investigation of Pharmacokinetics, Safety, and Tolerability of BAY 63-2521 in Male and Female Subjects With Hepatic Impairment (Classified as Child Pugh A or B) and in Age-, Weight- and Gender-matched Healthy Subjects Following a Single Oral Dose of 1 mg BAY 63-2521 in a Single-center, Non-randomized, Non-controlled, Non-blinded, Observational Study With Group Stratification

Conditions
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Clinical Pharmacology

Intervention / Treatment
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* Drug: Riociguat (Adempas, BAY 63-2521)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria for all subjects: Male and female White subjects 18 to ≤79 years of age, BMI between 18 and 34 kg/m^2 Women without childbearing potential or with childbearing potential but only if the pregnancy test is negative and are under highly effective contraception Inclusion criteria for subjects with liver cirrhosis: Documented liver cirrhosis confirmed by histopathology, eg previous liver biopsy, laparoscopy, or ultrasound Hepatic impairment (Child Pugh A or B) Stable liver disease Inclusion criteria for healthy subjects: - Age- (+/-10 years), weight- (+/-10 kg body weight), and gender-matched to a subject with liver cirrhosis as far as possible Exclusion criteria for all subjects: Febrile illness within 1 week before the start of the study Hypersensitivity to riociguat and / or to inactive constituents Smoking Exclusion criteria for subjects with liver cirrhosis: Hemoglobin <8 g/dL Severe cerebrovascular or cardiac disorders, eg myocardial infarction less than 6 months prior to dosing, congestive heart failure of NYHA grade III or IV, severe arrhythmia requiring antiarrhythmic treatment Evidence of hepatic encephalopathy related to chronic liver disease > Grade II Renal failure with a creatinine clearance <40 mL/min Resting heart rate in the awake subject below 45 BPM or above 100 BPM Systolic blood pressure (SBP) below 100 mmHg or above 160 mmHg, Diastolic blood pressure (DBP) above 95 mmHg Platelet count <30 x 10^9/L History of bleeding within the past 3 months AP >4 times the upper limit of normal (ULN) AST or ALT in conjunction with GGT >= 4 times the ULN (an isolated elevation of GGT >4 times ULN did not exclude the subject) Serum albumin <20 g/L Diabetes mellitus with a fasting blood glucose >220 mg/dL or HbA1c >10% Prothrombin time (Quick test) <30% Subjects who had undergone porto-caval shunt surgery Use of medications known to interfere with hepatic metabolism (eg cimetidine, barbiturates, phenothiazines, etc) or known to alter other major organs or systems within 30 days prior to dosing Severe infection, malignancy, psychosis, or any clinically significant illness within 4 weeks prior to dosing Concomitant use of any medication except medications necessary for the treatment of the kidney disease or related complications Concomitant use of phosphodiesterase-5 inhibitors, endothelin receptor antagonists (ERAs, eg bosentan), intravenous or inhalative prostacyclins, or nitrates Concomitant use of potent CYP3A4 and P-gp inhibitors Exclusion criteria for healthy subjects: Conspicuous findings in medical history or pre-study examination History of relevant diseases of vital organs, central nervous system, or other organs Resting heart rate in the awake subject below 45 BPM or above 90 BPM SBP below 100 mmHg or above 145 mmHg, DBP above 95 mmHg Regular daily consumption of more than 1 liter of usual beer or the equivalent quantity of approximately 40 g of alcohol in another form

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Riociguat, Child Pugh A<br>Participants with liver cirrhosis and mild hepatic impairment received a single dose of 1 mg (2 x 0.5 mg IR tablet) of riociguat in the fasted state | Drug: Riociguat (Adempas, BAY 63-2521)<br>* 0.5 mg riociguat as an immediate-release (IR) tablet<br>|
| Experimental: Riociguat, Child Pugh B<br>Participants with liver cirrhosis and moderate hepatic impairment received a single dose of 1 mg (2 x 0.5 mg IR tablet) of riociguat in the fasted state | Drug: Riociguat (Adempas, BAY 63-2521)<br>* 0.5 mg riociguat as an immediate-release (IR) tablet<br>|
| Experimental: Riociguat, control A<br>Healthy age-, weight-, and gender- matched participants to Child Pugh A group received a single dose of 1 mg (2 x 0.5 mg IR tablet) of riociguat in the fasted state | Drug: Riociguat (Adempas, BAY 63-2521)<br>* 0.5 mg riociguat as an immediate-release (IR) tablet<br>|
| Experimental: Riociguat, control B<br>Healthy age-, weight-, and gender- matched participants to Child Pugh B group received a single dose of 1 mg (2 x 0.5 mg IR tablet) of riociguat in the fasted state | Drug: Riociguat (Adempas, BAY 63-2521)<br>* 0.5 mg riociguat as an immediate-release (IR) tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC | Area under the plasma concentration vs time curve from zero to infinity for total (bound and unbound) drug after single dose for BAY 63-2521 and its metabolite M1 (BAY 60-4552) | Pre-dose and up to 72 hours post-dose, additionally up to 96 hours post-dose for Child Pugh B group only | 
| Cmax | Maximum total (bound and unbound) drug concentration in plasma after single dose administration for BAY 63-2521 and its metabolite M1 | Pre-dose and up to 72 hours post-dose, additionally up to 96 hours post-dose for Child Pugh B group only | 
| t½ | Half-life associated with the terminal slope for BAY 63-2521 and its metabolite M1 | Pre-dose and up to 72 hours post-dose, additionally up to 96 hours post-dose for Child Pugh B group only | 
| fu | Fraction unbound for BAY 63-2521 and its metabolite M1 | From 2 hours post-dose up to 24 hours post-dose | 
| AUCu | AUC for unbound drug for BAY 63-2521 and its metabolite M1 | From 2 hours post-dose up to 24 hours post-dose | 
| Cmax,u | Cmax for unbound drug for BAY 63-2521 and its metabolite M1 | From 2 hours post-dose up to 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC/D | AUC divided by dose (mg) for BAY 63-2521 and its metabolite M1 | Pre-dose and up to 72 hours post-dose, additionally up to 96 hours post-dose for Child Pugh B group only | 
| AUCnorm | AUC divided by dose (mg) per kg body weight for BAY 63-2521 and its metabolite M1 | Pre-dose and up to 72 hours post-dose, additionally up to 96 hours post-dose for Child Pugh B group only | 
| AUCu,norm | AUCnorm for unbound drug for BAY 63-2521 and its metabolite M1 | From 2 hours post-dose up to 24 hours post-dose | 
| AUC(0-tlast) | AUC from time 0 to the last data point for BAY 63-2521 and its metabolite M1 | Pre-dose and up to 72 hours post-dose, additionally up to 96 hours post-dose for Child Pugh B group only | 
| Cmax/D | Cmax divided by dose (mg) for BAY 63-2521 and its metabolite M1 | Pre-dose and up to 72 hours post-dose, additionally up to 96 hours post-dose for Child Pugh B group only | 
| Cmax,norm | Cmax divided by dose (mg) per kg body weight for BAY 63-2521 and its metabolite M1 | Pre-dose and up to 72 hours post-dose, additionally up to 96 hours post-dose for Child Pugh B group only | 
| Cmax,u,norm | Cmax,norm for unbound drug for BAY 63-2521 and its metabolite M1 | From 2 hours post-dose up to 24 hours post-dose | 
| tmax | Time to reach maximum drug concentration in plasma after single dose for BAY 63-2521 and its metabolite M1 | Pre-dose and up to 72 hours post-dose, additionally up to 96 hours post-dose for Child Pugh B group only | 
| MRT | Mean residence time for BAY 63-2521 and its metabolite M1 | Pre-dose and up to 72 hours post-dose, additionally up to 96 hours post-dose for Child Pugh B group only | 
| CL/F | Total body clearance of total (bound and unbound) drug from plasma calculated after oral administration (apparent oral clearance) for BAY 63-2521 and its metabolite M1 | Pre-dose and up to 72 hours post-dose, additionally up to 96 hours post-dose for Child Pugh B group only | 
| CLu/F | CL/F for unbound drug for BAY 63-2521 and its metabolite M1 | From 2 hours post-dose up to 24 hours post-dose | 
| Vz/F | Apparent volume of distribution during terminal phase after oral administration for BAY 63-2521 and its metabolite M1 | Pre-dose and up to 72 hours post-dose, additionally up to 96 hours post-dose for Child Pugh B group only | 
| AE,ur | Amount of (total) drug excreted in urine for BAY 63-2521 and its metabolite M1 | Pre-dose and up to 72 hours post-dose | 
| CLR | Renal body clearance of drug for BAY 63-2521 and its metabolite M1 | Pre-dose and up to 72 hours post-dose | 
| Number of participants with adverse events |  | Approximately 5 weeks |