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

NCT05112419 | Completed Phase 1 FDA Drug

• 2 other identifiers: D4326C000012021-003289-10
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Hepatic Impairment; Renal Impairment

Keywords

Renal Impairment; Hepatic Impairment; Healthy participants; Zibotentan; Pharmacokinetics; Safety

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (14)

• Number of participants with adverse events

  Screening (Day -28 to Day -2) to Day 6

• Time to reach maximum observed plasma concentration (tmax)

  Day 1 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

• Area under plasma concentration-time curve from time zero to 72 hours post-dose (AUC [0-72])

  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

Study Arms (2)

Cohort 1: Participants with moderate hepatic impairment and moderate renal impairment

EXPERIMENTAL

Participants will receive a single oral dose of zibotentan under fasted conditions.

Drug: Zibotentan

Cohort 2: Healthy participants

EXPERIMENTAL

Participants will receive a single oral dose of zibotentan under fasted conditions.

Drug: Zibotentan

Interventions

Zibotentan DRUG

All participants will receive a single oral dose of zibotentan capsule under fasted conditions.

Cohort 1: Participants with moderate hepatic impairment and moderate renal impairment; Cohort 2: Healthy participants

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).
• 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).

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (1)

Research Site

Sofia, 1612, Bulgaria

Location

Related Publications (1)

• Mercier AK, Sunnaker M, Ueckert S, Pawlik T, Henricson E, Molodetskyi O, Law GC, Parker VER, Oscarsson J. Pharmacokinetics and Tolerability of Zibotentan in Patients with Concurrent Moderate Renal and Moderate Hepatic Impairment. Clin Pharmacokinet. 2023 Dec;62(12):1713-1724. doi: 10.1007/s40262-023-01306-7. Epub 2023 Oct 6.

  PMID: 37801266 DERIVED

MeSH Terms

Conditions

Renal Insufficiency

Interventions

ZD4054

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: October 11, 2021
• First Posted: November 8, 2021
• Study Start: November 10, 2021
• Primary Completion: December 15, 2021
• Study Completion: December 15, 2021
• Last Updated: January 27, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

BU (1)