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
Overview
- Phase
- Phase 1
- Intervention
- Zibotentan
- Conditions
- Hepatic Impairment
- Sponsor
- AstraZeneca
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUClast)
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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).
Arms & Interventions
Cohort 1: Participants with moderate hepatic impairment and moderate renal impairment
Participants will receive a single oral dose of zibotentan under fasted conditions.
Intervention: Zibotentan
Cohort 2: Healthy participants
Participants will receive a single oral dose of zibotentan under fasted conditions.
Intervention: Zibotentan
Outcomes
Primary Outcomes
Area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUClast)
Time Frame: Day 1 to Day 6
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
Area under plasma concentration-time curve from time zero to infinity (AUCinf)
Time Frame: Day 1 to Day 6
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
Maximum observed plasma concentration (Cmax)
Time Frame: Day 1 to Day 6
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
Secondary Outcomes
- Apparent total non-renal body clearance of drug from plasma after extravascular administration (CLNR/F)(Day 1 to Day 6)
- Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz)(Day 1 to Day 6)
- Percentage of dose excreted unchanged in urine from time of dosing (time 0) through time t [fe (0-t)](Day 1 to Day 3)
- Time to reach maximum observed plasma concentration (tmax)(Day 1 to Day 6)
- Area under plasma concentration-time curve from time zero to 72 hours post-dose (AUC [0-72])(Day 1 to Day 6)
- Terminal elimination rate constant (λz)(Day 1 to Day 6)
- Amount of unchanged drug excreted into urine from time t1 to time t2 [Ae (t1-t2)](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)(Day 1 to Day 3)
- Number of participants with adverse events(Screening (Day -28 to Day -2) to Day 6)
- Area under the plasma concentration-time curve from time zero to 24 hours post-dose (AUC[0-24])(Day 1 to Day 6)
- Apparent total body clearance of drug from plasma after extravascular administration (CL/F)(Day 1 to Day 6)
- Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)(Day 1 to Day 6)
- Cumulative amount of unchanged drug excreted into urine from time of dosing (time 0) through time t [Ae (0-t)](Day 1 to Day 3)
- Percentage of dose excreted unchanged in urine from time t1 to time t2 [fe (t1-t2)](Day 1 to Day 3)