Hepatic Impairment Study With MDV3100 in Subjects With Mild and Moderate Hepatic Impairment Compared to a Healthy Control Group

Study Overview
=================
Brief Summary
-----------------
This study will assess the influence of hepatic impairment on the pharmacokinetics, safety and tolerability of a single dose of MDV3100 in male subjects. The study will consist of two treatment arms. Arm A will assess the influence of mild hepatic impairment, and Arm B will assess the influence of moderate hepatic impairment. Data obtained from subjects with hepatic impairment will be compared to data from Body Mass Index (BMI) and age-matched subjects with normal hepatic function.

Official Title
-----------------
A Phase I, Non-randomized, Open-label, Single-dose Study to Investigate the Pharmacokinetics, Safety and Tolerability of MDV3100 in Male Subjects With Mild or Moderate Hepatic Impairment and Normal Hepatic Function

Conditions
-----------------
Pharmacokinetics of MDV3100, Healthy Subjects, Kidney Diseases

Intervention / Treatment
-----------------
* Drug: MDV3100


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All subjects must meet all of the following inclusion criteria: Subject must be non-fertile, i.e., surgically sterilized or must practice an adequate contraceptive method to prevent pregnancies Body Mass Index (BMI) of at least 18.5 and no greater than 34.0 kg/m2. Subjects with mild or moderate hepatic impairment must also meet the following inclusion criteria: Child-Pugh classification Class A (mild, 5 or 6 points) or Class B (moderate, 7 to 9 points) liver function impairment. Exclusion Criteria: All subjects must not have any of the following characteristics: Known or suspected hypersensitivity to MDV3100 or any components of the formulation used. 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). Any clinically significant history of asthma, eczema, any other allergic condition or previous severe hypersensitivity to any drug (excluding non-active hay fever). Abnormal pulse and/or blood pressure (BP) measurements at the pre-study visit as follows: Pulse <40 or >90 bpm; mean systolic BP >160 mmHg; mean diastolic BP >100 mmHg (BP measurements taken in triplicate after subject has been resting in supine position for 5 min; pulse will be measured A QTcF interval of >450 ms after repeated measurements (consistently after duplicate measurements), a history of unexplained syncope, cardiac arrest, unexplained cardiac arrhythmias or torsades de pointes, structural heart disease, or a family history of Long QT Syndrome (LQTS). Significant renal dysfunction (creatinine clearance below 60 mL/min, estimated according to the method of modification of diet in renal disease (MDRD) formula). Regular use of any inducer of metabolism (e.g. barbiturates, rifampin) in the 3 months prior to admission to the Clinical Unit. Participation in any clinical study within 3 months or participation in more than 3 clinical studies within 12 months, prior to the expected date of enrolment into the study, provided that the clinical study did not entail a biological compound with a long terminal half life. For subjects with normal hepatic function: Regular use of any prescribed or OTC (over-the-counter) drugs, which includes vitamins, natural and herbal remedies (e.g. St John's wort) and food supplements in the 4 weeks prior to admission to the Clinical Unit and use of any drugs in the 2 weeks prior to admission to the Clinical Unit, except for occasional use of paracetamol (up to 3 g/day). Positive serology test for HBsAg, anti HAV (IgM), anti-HCV, anti-HIV-1 or anti-HIV-2. For subjects with mild or moderate hepatic impairment: 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. (e.g. advanced ascites, infection of ascites, fever, active gastrointestinal bleeding). Change in dose regimen of medically required medication within the last two weeks before pre-study examination (allowed co-medication in patients), and/or the use of unallowed co-medication in the 3 weeks prior to admission to the clinical unit (not allowed: any known hepatic enzyme altering agents or compounds known to restrict metabolism). Presence of a hepatocellular carcinoma, or an acute liver disease caused by an infection or drug toxicity. Severe portal hypertension or surgical porto-systemic shunts, including TIPSS (Transjugular intrahepatic portosystemic shunt). Biliary obstruction or other cause of hepatic impairment not related to parenchymal disorder and/or disease of the liver. Signs of significant hepatic encephalopathy (Hepatic encephalopathy score >2). Severe ascites and/or pleural effusion Esophageal variceal bleeding in the medical history. Thrombocyte level below 40x109/L and /or hemoglobin below 90 g/L. Previous liver transplantation. Positive serology test for, anti HAV (IgM), anti-HIV-1 or anti-HIV-2.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: Mild hepatic impairment subjects + control<br> | Drug: MDV3100<br>* Oral<br>* Other names: enzalutamide;|
| Experimental: B: Moderate hepatic impairment subjects + control<br> | Drug: MDV3100<br>* Oral<br>* Other names: enzalutamide;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of pharmacokinetics measured by AUC0-inf following single dose of MDV3100 | Area under the plasma concentration - time curve extrapolated to infinity (AUC0-inf) in subjects with mild and moderate hepatic impairment to matched control subjects with normal hepatic function. | Day 1 through Day 50 (25 times) | 
| Assessment of pharmacokinetics measured by Cmax following single dose of MDV3100 | Maximum concentration (observed) (Cmax) in subjects with mild and moderate hepatic impairment to matched control subjects with normal hepatic function. | Day 1 through Day 50 (25 times) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of pharmacokinetics following single dose of MDV3100 | Measured by 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), Cmax, t1/2, AUC0-inf, Unbound maximum concentration (observed) (Cmax,u), Unbound AUC extrapolated to infinity (AUC0-inf,u), Unbound apparent total body clearance after extra vascular dosing (CLu/F), Unbound apparent volume of distribution during the terminal phase after extra vascular dosing (Vz,u/F), Fraction unbound (fu). | Day 1 through Day 50 (25 times) | 
| Monitoring of safety and tolerability through assessment of vital signs, Electrocardiogram (ECG) and clinical safety laboratory and adverse events | For hepatic impaired subjects, additional Child-Pugh classification will be performed after MDV3100 administration. | Day 1 through Day 50 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Phase 1, MDV3100, Hepatic Impairment, Kidney Diseases, Xtandi, enzalutamide