Pharmacokinetics, Safety & Tolerability of ZD4054 (Zibotentan) in Subjects With Normal, Mild, Moderate and Severe Hepatic Impairment

An Open-label Comparative Study of the Pharmacokinetics, Safety and Tolerability of ZD4054 (Zibotentan) Following a 10 mg Single Oral Dose of ZD4054(Zibotentan) to Healthy Subjects and to Subjects With Mild, Moderate and Severe Hepatic Impairment

This study is designed to compare how ZD4054 (Zibotentan) is taken up, how it is broken down and removed from the body in subjects with liver cirrhosis and hepatic impairment compared to healthy subjects of a similar age, sex and weight. As for all clinical trials, safety and tolerability of the drug will be evaluated as well to develop dosing recommendations for dosing of ZD4054 (Zibotentan) in subjects with varying stages of hepatic impairment.

Study Overview

• Status: Completed
• Conditions: Hepatic Impairment
• Intervention / Treatment: Drug: ZD4054

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

Contacts and Locations

Study Locations

• Czech Republic
  • Praha 4, Czech Republic
    • Research Site
  • Praha 6, Czech Republic
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Hepatically impaired subjects - Subjects with stable liver cirrhosis and hepatic impairment for at least 3 months prior to the start of the study.
• Healthy volunteers - Clinical laboratory tests within the normal reference range or results with minor deviations which are not considered by the Investigator to be clinically significant

Exclusion Criteria:

• In the opinion of the investigator, any evidence of additional severe or uncontrolled systemic disease (eg, cardiac, or renal disease) or evidence of any other significant clinical disorder or laboratory finding
• Healthy volunteers - History or presence of hepatic disease known to interfere with absorption, distribution, metabolism or excretion of drug
• Hepatically impaired subjects - Fluctuating or rapidly deteriorating hepatic function as indicated by widely varying or worsening of clinical and/or laboratory signs of hepatic impairment within the screening period

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Control (healthy volunteers)	Drug: ZD4054; 10mg, Oral tablet, single dose; Other Names: Zibotentan
Experimental: 2; Mild Hepatic Impairment	Drug: ZD4054; 10mg, Oral tablet, single dose; Other Names: Zibotentan
Experimental: 3; Moderate Hepatic Impairment	Drug: ZD4054; 10mg, Oral tablet, single dose; Other Names: Zibotentan
Experimental: 4; Severe Hepatic Impairment	Drug: ZD4054; 10mg, Oral tablet, single dose; Other Names: Zibotentan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Characterise the pharmacokinetic profile of ZD4054 (Zibotentan) following a single 10 mg oral dose in subjects with normal hepatic function and in subjects with varying degrees of hepatic impairment.	predose and 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 hours post-dose

Secondary Outcome Measures

Outcome Measure	Time Frame
Assess the safety of Zibotentan following a single 10 mg oral dose in subjects with normal hepatic function and in subjects with varying degrees of hepatic impairment by assessment of vital signs, ECG, clinical chemistry, haematology and adverse events.	Predose until post-study medical
Explore changes in protein binding of Zibotentan and the subsequent effects on its pharmacokinetics in subjects with normal hepatic function and in subjects with varying degrees of hepatic impairment by assessment of free Cmax, free AUC and unbound CL/F.	3 hour post-dose

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: PRA Health Sciences
• Investigators: Principal Investigator: Blanka Cieslarova, MD, Medical Director & Head of Clinical Unit, PRA International

Publications and helpful links

General Publications

• Tomkinson H, Kemp J, Oliver S, Swaisland H, Taboada M, Morris T. Pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with hepatic or renal impairment: two open-label comparative studies. BMC Clin Pharmacol. 2011 Mar 17;11:3. doi: 10.1186/1472-6904-11-3.

Study record dates

Study Major Dates

• Study Start: April 1, 2008
• Study Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: May 1, 2008
• First Submitted That Met QC Criteria: May 1, 2008
• First Posted (Estimate): May 6, 2008

Study Record Updates

• Last Update Posted (Estimate): September 28, 2010
• Last Update Submitted That Met QC Criteria: September 27, 2010
• Last Verified: September 1, 2010

More Information

Terms related to this study

• Keywords: Hepatic Impairment
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases
• Other Study ID Numbers: D4320C00025; 4054IL/0025