A Study to Investigate the Effect of Severely Diminished Liver Function on the Metabolism, Safety, and Tolerability of a Single Oral Dose of Enzalutamide in Men
Primary Purpose
Severe Hepatic Impairment, Normal Hepatic Function
Status
Completed
Phase
Phase 1
Locations
Bulgaria
Study Type
Interventional
Intervention
enzalutamide
Sponsored by

About this trial
This is an interventional basic science trial for Severe Hepatic Impairment focused on measuring Phase 1, Pharmacokinetics, Safety, Severe hepatic impairment, Enzalutamide
Eligibility Criteria
Inclusion Criteria:
- Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control starting at Screening and continue throughout the study period and for 90 days after the final study drug administration.
- Male subject must not donate sperm starting at Screening and throughout the study period and for 90 days after the final study drug administration.
- Subject has a Body Mass Index (BMI) range of 18.5 - 34.0 kg/m2 inclusive. The subject weighs at least 50 kg [at Screening].
Inclusion Criteria:Subjects with severe hepatic impairment must also meet the following inclusion criteria:
- Subject has a Child-Pugh classification Class C (severe, 10 to 15 points).
Inclusion Criteria: For Healthy Subjects Only:
- Age- and BMI-matched to subjects with severe liver hepatic impairment.
Exclusion Criteria:
- Subject has known or suspected hypersensitivity to enzalutamide, or any components of the formulation used.
- Subject has history of seizure or any condition that may predispose to seizure. Also history of loss of consciousness or transient ischemic attack within 12 months of enrollment (Day 1 visit).
- Subject has used grapefruit (or grapefruit containing products) or marmalade in the week prior to admission to the clinical unit (Day -1), as reported by the subject.
Exclusion Criteria: For Healthy Subjects Only:
- Subject has any of the liver function tests above the upper limit of normal.
Exclusion Criteria: Subjects with severe hepatic impairment must also not have any of the following characteristics:
- Subject has fluctuating or rapidly deteriorating hepatic function, as indicated by strongly varying or worsening of clinical and/or laboratory signs of hepatic impairment within the screening period.
- Subject has surgical porto-systemic shunts, including TIPSS (Trans-jugular intrahepatic portosystemic shunt).
- Subject has presence of severe hepatic encephalopathy (grade > 2).
- Subject has advanced ascites.
- Subject has esophageal variceal bleeding in the medical history (within 6 months before Day -1).
- Subject has thrombocyte level below 40x109 /L and /or hemoglobin below 90 g/L.
- Subject has significant renal dysfunction (creatinine clearance below 50 mL/min, estimated according to the method of Modification of Diet in Renal Disease (MDRD) formula).
- Subject has had previous liver transplantation.
Sites / Locations
- Comac Medical Ltd.
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
1:Single dose of enzalutamide in hepatically impaired subjects
2:Single dose of enzalutamide in healthy subjects
Arm Description
Single dose of enzalutamide
Single dose of enzalutamide
Outcomes
Primary Outcome Measures
Pharmacokinetics (PK) of enzalutamide after a single oral dose
area under the plasma concentration - time curve (AUC) extrapolated to infinity (AUC0-inf)
PK of enzalutamide after a single oral dose
maximum concentration (observed) (Cmax)
PK of enzalutamide plus N-desmethyl enzalutamide (M2) after a single oral dose
area under the plasma concentration - time curve (AUC) extrapolated to infinity (AUC0-inf)
PK of enzalutamide plus N-desmethyl enzalutamide (M2) after a single oral dose
maximum concentration (observed) (Cmax)
Secondary Outcome Measures
PK of enzalutamide, M1, M2 and the sum of enzalutamide plus N-desmethyl enzalutamide (M2)
Cmax and AUC0-inf (M1, M2 only), time to attain Cmax (tmax), AUC up to last quantifiable concentration (AUC0-last), apparent terminal elimination half life (t1/2), apparent volume of distribution during the terminal phase after extra vascular dosing (Vz/F), apparent total body clearance after extra vascular dosing (CL/F) (parent compound only), Metabolite-to-Parent Ratio (MPR), percent extrapolated for AUC0-inf (%AUC)
Additional pharmacokinetic variables for enzalutamide, and, as appropriate, for M1 and M2, based upon unbound plasma concentrations
Unbound Cmax (Cmax,u), unbound AUC0-inf (AUC0-inf,u), and unbound AUC0-last (AUC0-last,u). Unbound CL/F (CLu/F) and unbound Vz/F (Vz,u/F) (parent only)
Full Information
NCT ID
NCT02138162
First Posted
May 12, 2014
Last Updated
May 12, 2014
Sponsor
Astellas Pharma Europe B.V.
Collaborators
Medivation, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT02138162
Brief Title
A Study to Investigate the Effect of Severely Diminished Liver Function on the Metabolism, Safety, and Tolerability of a Single Oral Dose of Enzalutamide in Men
Official Title
A Phase 1, Non-randomized, Open-label, Single-dose Study to Investigate the Pharmacokinetics, Safety and Tolerability of Enzalutamide in Male Subjects With Severe Hepatic Impairment and Normal Hepatic Function
Study Type
Interventional
2. Study Status
Record Verification Date
May 2014
Overall Recruitment Status
Completed
Study Start Date
August 2013 (undefined)
Primary Completion Date
March 2014 (Actual)
Study Completion Date
March 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Astellas Pharma Europe B.V.
Collaborators
Medivation, Inc.
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The influence of severely diminished liver function on the metabolism, safety, and tolerability of a single oral dose of enzalutamide in a group of 8 men. The results are compared to the data gained from 8 age- and BMI-matched men with normal liver function.
Detailed Description
Screening takes place between Day -22 and Day -2, and subjects are admitted to the clinic on Day -1. Each subject receives a single oral dose of enzalutamide on Day 1, under fasted conditions. They are discharged on Day 7; ambulant visits take place until Day 50. An End of Study Visit (ESV) occurs 7-10 days after the last PK sampling or early withdrawal.
Full PK profiles are obtained for enzalutamide, metabolite 1 of enzalutamide (M1) and metabolite 2 of enzalutamide (M2) up to 1176 hours (Day 50) after administration.
Safety assessments are performed throughout the study. For subjects with severe hepatic impairment, additional Child-Pugh classification and laboratory safety tests (including liver function tests) are performed regularly after administration.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Severe Hepatic Impairment, Normal Hepatic Function
Keywords
Phase 1, Pharmacokinetics, Safety, Severe hepatic impairment, Enzalutamide
7. Study Design
Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
16 (Actual)
8. Arms, Groups, and Interventions
Arm Title
1:Single dose of enzalutamide in hepatically impaired subjects
Arm Type
Experimental
Arm Description
Single dose of enzalutamide
Arm Title
2:Single dose of enzalutamide in healthy subjects
Arm Type
Experimental
Arm Description
Single dose of enzalutamide
Intervention Type
Drug
Intervention Name(s)
enzalutamide
Other Intervention Name(s)
ASP9785,, MDV3100,, Xtandi
Intervention Description
oral
Primary Outcome Measure Information:
Title
Pharmacokinetics (PK) of enzalutamide after a single oral dose
Description
area under the plasma concentration - time curve (AUC) extrapolated to infinity (AUC0-inf)
Time Frame
Days 1-6, 8, 12, 15, 19, 22, 26, 29, 36, 43, 50
Title
PK of enzalutamide after a single oral dose
Description
maximum concentration (observed) (Cmax)
Time Frame
Days 1-6, 8, 12, 15, 19, 22, 26, 29, 36, 43, 50
Title
PK of enzalutamide plus N-desmethyl enzalutamide (M2) after a single oral dose
Description
area under the plasma concentration - time curve (AUC) extrapolated to infinity (AUC0-inf)
Time Frame
Days 1-6, 8, 12, 15, 19, 22, 26, 29, 36, 43, 50
Title
PK of enzalutamide plus N-desmethyl enzalutamide (M2) after a single oral dose
Description
maximum concentration (observed) (Cmax)
Time Frame
Days 1-6, 8, 12, 15, 19, 22, 26, 29, 36, 43, 50
Secondary Outcome Measure Information:
Title
PK of enzalutamide, M1, M2 and the sum of enzalutamide plus N-desmethyl enzalutamide (M2)
Description
Cmax and AUC0-inf (M1, M2 only), time to attain Cmax (tmax), AUC up to last quantifiable concentration (AUC0-last), apparent terminal elimination half life (t1/2), apparent volume of distribution during the terminal phase after extra vascular dosing (Vz/F), apparent total body clearance after extra vascular dosing (CL/F) (parent compound only), Metabolite-to-Parent Ratio (MPR), percent extrapolated for AUC0-inf (%AUC)
Time Frame
Days 1-6, 8, 12, 15, 19, 22, 26, 29, 36, 43, 50
Title
Additional pharmacokinetic variables for enzalutamide, and, as appropriate, for M1 and M2, based upon unbound plasma concentrations
Description
Unbound Cmax (Cmax,u), unbound AUC0-inf (AUC0-inf,u), and unbound AUC0-last (AUC0-last,u). Unbound CL/F (CLu/F) and unbound Vz/F (Vz,u/F) (parent only)
Time Frame
Days 1-6, 8, 12, 15, 19, 22, 26, 29, 36, 43, 50
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
69 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control starting at Screening and continue throughout the study period and for 90 days after the final study drug administration.
Male subject must not donate sperm starting at Screening and throughout the study period and for 90 days after the final study drug administration.
Subject has a Body Mass Index (BMI) range of 18.5 - 34.0 kg/m2 inclusive. The subject weighs at least 50 kg [at Screening].
Inclusion Criteria:Subjects with severe hepatic impairment must also meet the following inclusion criteria:
Subject has a Child-Pugh classification Class C (severe, 10 to 15 points).
Inclusion Criteria: For Healthy Subjects Only:
Age- and BMI-matched to subjects with severe liver hepatic impairment.
Exclusion Criteria:
Subject has known or suspected hypersensitivity to enzalutamide, or any components of the formulation used.
Subject has history of seizure or any condition that may predispose to seizure. Also history of loss of consciousness or transient ischemic attack within 12 months of enrollment (Day 1 visit).
Subject has used grapefruit (or grapefruit containing products) or marmalade in the week prior to admission to the clinical unit (Day -1), as reported by the subject.
Exclusion Criteria: For Healthy Subjects Only:
Subject has any of the liver function tests above the upper limit of normal.
Exclusion Criteria: Subjects with severe hepatic impairment must also not have any of the following characteristics:
Subject has fluctuating or rapidly deteriorating hepatic function, as indicated by strongly varying or worsening of clinical and/or laboratory signs of hepatic impairment within the screening period.
Subject has surgical porto-systemic shunts, including TIPSS (Trans-jugular intrahepatic portosystemic shunt).
Subject has presence of severe hepatic encephalopathy (grade > 2).
Subject has advanced ascites.
Subject has esophageal variceal bleeding in the medical history (within 6 months before Day -1).
Subject has thrombocyte level below 40x109 /L and /or hemoglobin below 90 g/L.
Subject has significant renal dysfunction (creatinine clearance below 50 mL/min, estimated according to the method of Modification of Diet in Renal Disease (MDRD) formula).
Subject has had previous liver transplantation.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Astellas Pharma Europe B.V.
Official's Role
Study Director
Facility Information:
Facility Name
Comac Medical Ltd.
City
Sofia
ZIP/Postal Code
1612
Country
Bulgaria
12. IPD Sharing Statement
Learn more about this trial
A Study to Investigate the Effect of Severely Diminished Liver Function on the Metabolism, Safety, and Tolerability of a Single Oral Dose of Enzalutamide in Men
We'll reach out to this number within 24 hrs