A Study to Assess Zibotentan Pharmacokinetics in Participants With Moderate Hepatic and Moderate Renal Impairment

Study Overview
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Brief Summary
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This study will evaluate the pharmacokinetics (PK), safety, and tolerability of a single oral dose of zibotentan in patients with moderate hepatic and moderate renal impairment in comparison to a matched healthy control group.

Detailed Description
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This is a single-dose, non-randomised, open-label, parallel-group study. All participants will receive a single oral dose of 5 mg zibotentan under fasted conditions and will be involved in the study for approximately 5 weeks. Approximately 12 participants will be enrolled into each one of the 2 cohorts and receive the study intervention: Cohort 1: 12 participants with moderate hepatic impairment and moderate renal impairment as assessed at Screening Cohort 2: 12 healthy participants matched for age (± 10 years), gender, and BMI (± 20%) on a group level to participants in Cohort 1 The study will comprise of the following study periods: A Screening Period of maximum 28 days (before dosing): participants will be screened for eligibility. A Residential Period of 8 days: participants will be admitted to the study centre in the evening on Day 2, two days before administration of a single oral dose of zibotentan (Day 1). Participants will have final study assessments on Day 6 (120 hours post-dose) and will be discharged that day.

Official Title
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A Single Dose, Non-Randomised, Open-Label, Parallel-Group Study to Investigate the Pharmacokinetics, Safety, and Tolerability of Zibotentan in Healthy Participants Compared to Participants With Moderate Hepatic and Moderate Renal Impairment

Conditions
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Hepatic Impairment, Renal Impairment

Intervention / Treatment
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* Drug: Zibotentan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body weight of at least 50 kg and body mass index within the range of 18 and 35 kg/m^2 (inclusive). Female of non-childbearing potential or male Participants with Moderate Hepatic Impairment and Moderate Renal Impairment only (Cohort 1) An estimated glomerular filtration rate (eGFR) in the range of 30 to 45 mL/min/1.73m^2 (inclusive) as determined using the Chronic Kidney Disease Epidemiology Collaboration formula, at Screening. Retesting for eGFR may be repeated twice during Screening Period. Confirmed clinical diagnosis of cirrhosis with either ascites or moderate hepatic impairment (Childs-Pugh B). Supporting documents confirming the participant's hepatic impairment must be available. The participant must be classified by the Investigator or usual practitioner as Child-Pugh Class B or having radiographic or clinical evidence of ascites of any grade. Stable hepatic impairment (eg, no clinically significant change in signs, symptoms, or laboratory parameters of hepatic disease status within 28 days prior to Screening, as determined by the Investigator or usual practitioner). Healthy Participants only (Cohort 2) Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, and clinical laboratory tests. An eGFR of ≥ 90 mL/min/1.73m^2 as determined using the CKD-EPI formula at Screening. No clinically significant liver or kidney disease as judged by the Investigator. Exclusion Criteria: Medical Conditions Any evidence of a clinically significant disease which in the Investigator's opinion makes it undesirable for the participant to participate in the study. History of alcohol abuse or excessive intake of alcohol within 6 months prior to the Screening visit. Definition of excessive intake: an average weekly intake of >7 drinks/week for men or > 3.5 drinks/week for women. One drink is equivalent to (16 g of alcohol). Positive alcohol or drug of abuse at Screening. Participants with a history of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the Investigator, to drugs with a similar chemical structure or class to zibotentan. Participants with known hypersensitivity/allergic reaction to paracetamol. Any signs or confirmation of coronavirus disease-19 infection. Participants with Moderate Hepatic Impairment and Moderate Renal Impairment only (Cohort 1) Presence of unstable medical (eg, diabetes, epilepsy) or psychological conditions which, in the opinion of the Investigator, would compromise the participant's safety or successful participation in this study. Fluctuating or rapidly deteriorating hepatic function, as indicated by strongly varying or worsening of clinical and/or laboratory signs of hepatic impairment within 28 days prior to dosing (eg, infection of ascites, fever, or active gastrointestinal bleeding). Severe hepatic impairment (Child-Pugh Class C Hepatic impairment), an isolated aspartate aminotransferase (AST) or alanine aminotransferase (ALT)> 5 x the upper limit of normal (ULN); or total bilirubin > 2 x ULN at time of enrolment or a concurrent increased AST and ALT of > 3 x the ULN together with a total bilirubin of > 2 x ULN. An isolated increase in bilirubin in participants with known Gilbert's syndrome is not a reason for exclusion. Acute liver disease caused by drug toxicity or by an infection. Presence of a hepatocellular carcinoma. Liver or renal transplantation or planned within the next 3 months at Screening. Receiving renal replacement therapy. Recent acute or subacute renal function deterioration (eg, participants with large fluctuations of creatinine values, as judged by the Investigator, and documented within 28 days prior to Screening). New York Heart Association functional heart failure Class III or intravenous or with unstable heart failure requiring hospitalisation for optimisation of heart failure treatment and who are not yet stable on heart failure therapy within 6 months prior to Screening. Abnormal resting vital signs (after resting for 10 minutes) of supine systolic blood pressure> 180 mmHg or < 100 Hg; or diastolic blood pressure> 110 mmHg or < 50 mmHg. Change in dose regimen of medically-required medication within the 14 days before dosing. Healthy Participants only (Cohort 2) - History of any clinically important disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the participant's ability to participate in the study. Prior/Concomitant Therapy Use of strong or moderate inhibitors or inducers of CYP3A4 within 28 days prior to dose of zibotentan. Use of phosphate binders (eg, aluminium hydroxide and calcium carbonate) and acid reducing agents such as cholestyramine/colestipol, ranitidine/nizatidine, or proton pump inhibitors within 3 days before and 12 hours after dosing with zibotentan.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two cohorts (patients and matched healthy subjects) to be enrolled for this study. Approximately 12 participants will be enrolled into each one of the 2 cohorts and receive the study intervention: Cohort 1 will enroll participants with moderate hepatic impairment and moderate renal impairment as assessed at screening. Cohort 2 will enroll healthy participants
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Participants with moderate hepatic impairment and moderate renal impairment<br>Participants will receive a single oral dose of zibotentan under fasted conditions. | Drug: Zibotentan<br>* All participants will receive a single oral dose of zibotentan capsule under fasted conditions.<br>|
| Experimental: Cohort 2: Healthy participants<br>Participants will receive a single oral dose of zibotentan under fasted conditions. | Drug: Zibotentan<br>* All participants will receive a single oral dose of zibotentan capsule under fasted conditions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under plasma concentration-time curve from time zero to infinity (AUCinf) | To assess the PK of a single oral dose of zibotentan in participants with moderate hepatic impairment and moderate renal impairment compared to a group of healthy matched controls | Day 1 to Day 6 | 
| Area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUClast) | To assess the PK of a single oral dose of zibotentan in participants with moderate hepatic impairment and moderate renal impairment compared to a group of healthy matched controls | Day 1 to Day 6 | 
| Maximum observed plasma concentration (Cmax) | To assess the PK of a single oral dose of zibotentan in participants with moderate hepatic impairment and moderate renal impairment compared to a group of healthy matched controls | Day 1 to Day 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events | To evaluate the safety and tolerability of a single oral dose of zibotentan in participants with moderate hepatic impairment and moderate renal impairment compared to a group of healthy matched controls | Screening (Day -28 to Day -2) to Day 6 | 
| Time to reach maximum observed plasma concentration (tmax) | To further characterise zibotentan plasma PK in all treatment groups | Day 1 to Day 6 | 
| Area under the plasma concentration-time curve from time zero to 24 hours post-dose (AUC[0-24]) | To further characterise zibotentan plasma PK in all treatment groups | Day 1 to Day 6 | 
| Area under plasma concentration-time curve from time zero to 72 hours post-dose (AUC [0-72]) | To further characterise zibotentan plasma PK in all treatment groups | Day 1 to Day 6 | 
| Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz) | To further characterise zibotentan plasma PK in all treatment groups | Day 1 to Day 6 | 
| Terminal elimination rate constant (λz) | To further characterise zibotentan plasma PK in all treatment groups | Day 1 to Day 6 | 
| Apparent total body clearance of drug from plasma after extravascular administration (CL/F) | To further characterise zibotentan plasma PK in all treatment groups | Day 1 to Day 6 | 
| Apparent total non-renal body clearance of drug from plasma after extravascular administration (CLNR/F) | To further characterise zibotentan plasma PK in all treatment groups | Day 1 to Day 6 | 
| Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) | To further characterise zibotentan plasma PK in all treatment groups | Day 1 to Day 6 | 
| Amount of unchanged drug excreted into urine from time t1 to time t2 [Ae (t1-t2)] | To further characterise zibotentan urine PK in all treatment groups | Day 1 to Day 3 | 
| Cumulative amount of unchanged drug excreted into urine from time of dosing (time 0) through time t [Ae (0-t)] | To further characterise zibotentan urine PK in all treatment groups | Day 1 to Day 3 | 
| Percentage of dose excreted unchanged in urine from time t1 to time t2 [fe (t1-t2)] | To further characterise zibotentan urine PK in all treatment groups | Day 1 to Day 3 | 
| Percentage of dose excreted unchanged in urine from time of dosing (time 0) through time t [fe (0-t)] | To further characterise zibotentan urine PK in all treatment groups | Day 1 to Day 3 | 
| Renal clearance of drug from plasma, calculated as Ae0-t/AUC0-t where t is matched for urine and plasma (CLR) | To further characterise zibotentan urine PK in all treatment groups | Day 1 to Day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal Impairment, Hepatic Impairment, Healthy participants, Zibotentan, Pharmacokinetics, Safety