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

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

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

Study Overview

• Status: Completed
• Conditions: Clinical Pharmacology
• Intervention / Treatment: Drug: Riociguat (Adempas, BAY 63-2521)

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Schleswig-Holstein
    • Kiel, Schleswig-Holstein, Germany, 24105

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Riociguat, Child Pugh A; 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); 0.5 mg riociguat as an immediate-release (IR) tablet
EXPERIMENTAL: Riociguat, Child Pugh B; 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); 0.5 mg riociguat as an immediate-release (IR) tablet
EXPERIMENTAL: Riociguat, control A; 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); 0.5 mg riociguat as an immediate-release (IR) tablet
EXPERIMENTAL: Riociguat, control B; 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); 0.5 mg riociguat as an immediate-release (IR) tablet

What is the study measuring?

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
Number of participants with adverse events		Approximately 5 weeks
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

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

Helpful Links

• Click here to find results for studies related to Bayer products

Study record dates

Study Major Dates

• Study Start: April 14, 2010
• Primary Completion (ACTUAL): April 28, 2011
• Study Completion (ACTUAL): September 15, 2011

Study Registration Dates

• First Submitted: April 23, 2020
• First Submitted That Met QC Criteria: April 25, 2020
• First Posted (ACTUAL): April 29, 2020

Study Record Updates

• Last Update Posted (ACTUAL): April 29, 2020
• Last Update Submitted That Met QC Criteria: April 25, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Activators; Riociguat
• Other Study ID Numbers: 15001; 2009-017684-42 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Availability of this study's data will be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the Study sponsors section of the portal.