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

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

A study to assess possible drug-drug interactions between MDV3100 and gemfibrozil and MDV3100 and Itraconazole.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects; Pharmacokinetics; Drug-Drug Interaction
• Intervention / Treatment: Drug: Itraconazole; Drug: MDV3100; Drug: Gemfibrozil

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • SGS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1: MDV3100	Drug: MDV3100; Oral; Other Names: Xtandi; ASP9785; enzalutamide
Experimental: 2: MDV3100 and gemfibrozil	Drug: MDV3100; Oral; Other Names: Xtandi; ASP9785; enzalutamide; Drug: Gemfibrozil; Oral
Experimental: 3: MDV3100 and itraconazole	Drug: Itraconazole; Oral; Drug: MDV3100; Oral; Other Names: Xtandi; ASP9785; enzalutamide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Astellas Pharma Europe B.V.
• Collaborators: Medivation, Inc.

Publications and helpful links

General Publications

• Gibbons JA, de Vries M, Krauwinkel W, Ohtsu Y, Noukens J, van der Walt JS, Mol R, Mordenti J, Ouatas T. Pharmacokinetic Drug Interaction Studies with Enzalutamide. Clin Pharmacokinet. 2015 Oct;54(10):1057-69. doi: 10.1007/s40262-015-0283-1.

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: July 30, 2013
• First Submitted That Met QC Criteria: July 30, 2013
• First Posted (Estimate): August 1, 2013

Study Record Updates

• Last Update Posted (Estimate): August 1, 2013
• Last Update Submitted That Met QC Criteria: July 30, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: Phase 1; Xtandi; MDV3100; enzalutamide; Itraconazole; Gemfibrozil
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antimetabolites; Hormones, Hormone Substitutes, and Hormone Antagonists; Hypolipidemic Agents; Lipid Regulating Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C8 Inhibitors; Itraconazole; Gemfibrozil
• Other Study ID Numbers: 9785-CL-0006; 2011-000333-37 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No