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 Renal Impairment 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 Renal Impairment and in Age- and Weight- 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 with 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 renal failure: - Stable renal disease, ie. a serum creatinine value determined at least 3 - 6 months before the pre-study visit was not allowed to vary by more than 20% from the serum creatinine value determined at the pre-study visit Inclusion criteria for healthy subjects: - Mean age and body weight not allowed to vary by more than +/- 10 years and +/- 10 kg from the subjects with renal impairment, respectively 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 renal failure: Resting heart rate in the awake subject below 45 BPM or above 90 BPM Acute renal failure or nephritis Any organ transplant Diastolic blood pressure (DBP) >100 mmHg and / or systolic blood pressure (SBP) >180 mmHg Hemoglobin <8 g/dL, Proteinuria >8 g/24 hours, Serum albumin <30 g/L, Platelet count <100 x 109/L History of bleeding within the past 3 months Diabetes mellitus with a fasting blood glucose >220 mg/dL or HbA1c >10% 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 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 SBP below 100 mmHg or above 145 mmHg and / or 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, healthy participants<br>Participants with creatinine clearance (CLCR) >80 mL/min 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, mild renal impairment<br>Participants with CLCR 50-80 mL/min 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, moderate renal impairment<br>Participants with CLCR 30-<50 mL/min 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, severe renal impairment<br>Participants with CLCR <30 mL/min 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 up to 72 hours post-dose | 
| Cmax | Maximum total (bound and unbound) drug concentration in plasma after single dose administration for BAY 63-2521 and its metabolite M1 | Pre-dose up to 72 hours post-dose | 
| t½ | Half-life associated with the terminal slope for BAY 63-2521 and its metabolite M1 | Pre-dose up to 72 hours post-dose | 
| 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 for BAY 63-2521 and its metabolite M1 | Pre-dose up to 72 hours post-dose | 
| AUCnorm | AUC divided by dose per kg body weight for BAY 63-2521 and its metabolite M1 | Pre-dose up to 72 hours post-dose | 
| 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 up to 72 hours post-dose | 
| Cmax/D | Cmax divided by dose for BAY 63-2521 and its metabolite M1 | Pre-dose up to 72 hours post-dose | 
| Cmax,norm | Cmax divided by dose per kg body weight for BAY 63-2521 and its metabolite M1 | Pre-dose up to 72 hours post-dose | 
| 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 Cmax (in case of two identical Cmax values, the first tmax was used) for BAY 63-2521 and its metabolite M1 | Pre-dose up to 72 hours post-dose | 
| MRT | Mean residence time for BAY 63-2521 and its metabolite M1 | Pre-dose up to 72 hours post-dose | 
| CL/F | Total body clearance of drug calculated after extravascular administration (eg apparent oral clearance) for BAY 63-2521 and its metabolite M1 | Pre-dose up to 72 hours post-dose | 
| 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 extravascular administration for BAY 63-2521 and its metabolite M1 | Pre-dose up to 72 hours post-dose | 
| AE,ur | Amount of (total) drug excreted in urine for BAY 63-2521 and its metabolite M1 | From 24 hours prior to drug administration up to 72 hours post-dose | 
| CLR | Renal body clearance of drug for BAY 63-2521 and its metabolite M1 | From 24 hours prior to drug administration up to 72 hours post-dose | 
| Number of participants with adverse events |  | Approximately 5 weeks |