Drug-drug Interaction Study With MDV3100 (ASP9785) and Gemfibrozil and Itraconazole

Study Overview
=================
Brief Summary
-----------------
A study to assess possible drug-drug interactions between MDV3100 and gemfibrozil and MDV3100 and Itraconazole.

Official Title
-----------------
A Phase I Randomized, Open-label, 3-arm Parallel-design Study to Determine the Effect of Multiple-dose Gemfibrozil or Itraconazole on the Pharmacokinetics, Safety and Tolerability of Single-dose MDV3100 (ASP9785) in Healthy Male Subjects

Conditions
-----------------
Healthy Subjects, Pharmacokinetics, Drug-Drug Interaction

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Body weight of at least 65.0 kg and no greater than 85.0 kg. Body Mass Index (BMI) of at least 18.5 and no greater than 30.0 kg/m2. Exclusion Criteria: Known or suspected hypersensitivity to MDV3100, itraconazole, gemfibrozil, any components of the formulations used, or any history of liver toxicity with other drugs. Confirmed CYP2C8 PM status based on genotyping analysis. Any of the liver function tests above the upper limit of normal. A retest to confirm the result may be performed once. History of seizure, including any febrile seizure, loss of consciousness, or transient ischemia attack within 12 months prior to enrollment (Day 1 visit), or any condition that may pre-dispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization). 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 >140 mmHg ; mean diastolic BP >90 mmHg (BP measurements taken in triplicate after subject has been resting in supine position for 5 min; pulse will be measured automatically). A QTc interval of >430 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). Regular use of any inducer of metabolism (e.g. barbiturates, rifampin) in the 3 months prior to admission to the Clinical Unit. Positive serology test for HBsAg, anti HAV (IgM), anti-HCV or anti-HIV 1+2.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1: MDV3100<br> | Drug: MDV3100<br>* Oral<br>* Other names: enzalutamide;|
| Experimental: 2: MDV3100 and gemfibrozil<br> | Drug: MDV3100<br>* Oral<br>* Other names: enzalutamide;Drug: Gemfibrozil<br>* Oral<br>|
| Experimental: 3: MDV3100 and itraconazole<br> | Drug: MDV3100<br>* Oral<br>* Other names: enzalutamide;Drug: Itraconazole<br>* Oral<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of pharmacokinetic profile of MDV3100 by Cmax (Maximum concentration) |  | Day 1 through Day 53 (29 times) | 
| Assessment of pharmacokinetic profile of MDV3100 by AUCinf (AUC extrapolated to infinity) |  | Day 1 through Day 53 (29 times) | 
| Assessment of pharmacokinetic profile of MDV3100 by AUC0-432h (AUC from the time of dosing to 432 hours post-dose) |  | Day 1 through Day 53 (29 times) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of pharmacokinetic profile of MDV3100 | tmax (Time to attain Cmax), t1/2 (Apparent terminal elimination half life), Vz/F (Apparent volume of distribution during the terminal phase after extra vascular dosing) and CL/F(Apparent total body clearance after extra vascular dosing) | Day 1 through Day 53 (29 times) | 
| Assessment of pharmacokinetic profile of the metabolites MDPC0001 and MDPC0002 | Cmax, AUC0-432h, tmax, t1/2, and AUC0-inf | Day 1 through Day 53 (29 times) | 
| Assessment of metabolite-to-parent ratios for MDV3100 | This may additionally be reported to assess effects on particular enzyme pathways | Day 1 through Day 53 (29 times) | 
| Assessment of Gemfibrozil and gemfibrozil 1-O-β-glucuronide (Arm 2) | Cmax, C0h, Cmin, tmax, AUCtau | Day 1 through Day 53 (50 times) | 
| Assessment of itraconazole and hydroxyitraconazole (Arm 3) | Cmax, C0h, Cmin, tmax, AUCtau | Day 1 through Day 53 (50 times) | 
| Safety as assessed by recording adverse events, laboratory assessments, vital signs and electrocardiograms (ECGs) | In arm 3, liver function tests (AST, ALT, GGT, total bilirubin) will be done regularly during itraconazole dosing | Day 1 through Day 53 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Phase 1, MDV3100, Gemfibrozil, Itraconazole, Xtandi, enzalutamide