A Study to Evaluate How a Drug That Alters Liver Enzymes (Rifampin) Affects the Metabolism of Enzalutamide in Men

A Phase I, Randomized, Open-label, 2-arm Parallel-design Study to Determine the Effect of Multiple-dose Rifampin on the Pharmacokinetics, Safety and Tolerability of Single-dose Enzalutamide in Healthy Male Subjects

This study evaluates how a drug that alters liver enzymes (rifampin) affects the metabolism of enzalutamide in men by measuring concentrations of enzalutamide and its metabolites in plasma.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects; Drug-Drug Interaction (DDI); Pharmacokinetics of Enzalutamide
• Intervention / Treatment: Drug: enzalutamide; Drug: rifampin

Detailed Description

The study consists of 2 randomized treatment arms. In both arms the subjects receive a single oral dose of enzalutamide.

In Arm 1 the subjects are admitted to the clinic on Day -1 where they remain until Day 3. Each subject receives a single oral dose of enzalutamide, administered under fasted conditions on Day 1. Ambulant visits take place from Day 4 to Day 50. Full PK profiles are obtained for enzalutamide, Major Inactive Carboxylic Acid Metabolite (M1) and Active Metabolite N-desmethyl Enzalutamide (M2) from Day 1 up to Day 50 after intake of enzalutamide.

In Arm 2 each subject receives a once-daily dose of rifampin on Days 1 to 21. On Day 8, a single oral dose of enzalutamide is administered under fasted conditions concomitantly with rifampin. Full PK profiles are obtained for enzalutamide, M1 and M2 from Day 8 up to Day 57 after intake of enzalutamide.

An End of Study Visit (ESV) takes place between 7 and 10 days after the last PK sample or early withdrawal.

Safety assessments are performed throughout the study.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 14050
    • Parexel International GmbH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Subject has a Body Mass Index (BMI) of at least 18.5 and no greater than 29.9 kg/m2 at screening.
• Subject must use a condom when having sex with a pregnant woman.
• 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.
• Male subject must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration.

Exclusion Criteria:

• Subject has a confirmed CYP2C8 poor metabolizer status based on genotyping analysis.
• Subject has a history of seizure or any condition that may predispose to seizure. Historically or currently on any convulsive medication or drugs that may lower the seizure threshold. History of any central nervous system (CNS) infections. Also history of transient ischemic attack or cerebrovascular accident with or without head trauma within 12 months of enrollment (Day -1 visit).
• Subject has any significant blood loss, donated one unit (450 mL) of blood or more, or received a transfusion of any blood or blood products within 60 days or donated plasma within 7 days prior to clinic admission on Day -1.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1: single dose of enzalutamide	Drug: enzalutamide; oral; Other Names: Xtandi; ASP9785,; MDV3100,
EXPERIMENTAL: 2: multiple doses of rifampin and single dose of enzalutamide	Drug: enzalutamide; oral; Other Names: Xtandi; ASP9785,; MDV3100,; Drug: rifampin; oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
PK of enzalutamide and the sum of enzalutamide + M2 in plasma measured by area under the curve (AUC) from time 0 to 336 hours after dosing (AUC0-336h)	Days 1 to 50 (29 times)
PK of enzalutamide and the sum of enzalutamide + M2 in plasma measured by AUC extrapolated to infinity (AUCinf)	Days 1 to 50 (29 times)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK of enzalutamide, M2, M1 and the sum of enzalutamide + M2 in plasma	AUC0-336h, AUCinf, Cmax (M2, M1), time to attain Cmax (tmax), terminal elimination half life (t1/2), AUC up to last quantifiable concentration (AUClast), apparent total body clearance after extra vascular dosing (CL/F), apparent volume of distribution during the terminal phase after extra vascular dosing (Vz/F) (parent compound only), Metabolite-to-Parent Ratio (MPR), percent extrapolated for AUCinf (%AUC)	Days 8 to 57 (49 times)
PK of rifampin in plasma	Cmax, tmax, AUC for the defined interval between doses (AUCtau), minimum concentration (Cmin)	Days 6 to 21 (20 times)
Safety and tolerability of enzalutamide, alone or in the presence of rifampin	vital signs, incidence of adverse events (AE), laboratory assessments, physical examination, electrocardiogram (ECG)	Screening (Day -28 to -7) to End of Study Visit (ESV) (>34 times)

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• Link to Results on JAPIC - enter 140632 in the JapicCTI-RNo. field

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (ACTUAL): September 1, 2013
• Study Completion (ACTUAL): September 1, 2013

Study Registration Dates

• First Submitted: May 13, 2014
• First Submitted That Met QC Criteria: May 13, 2014
• First Posted (ESTIMATE): May 15, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): October 15, 2014
• Last Update Submitted That Met QC Criteria: October 14, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: Safety; Pharmacokinetics; Phase I; Enzalutamide; Rifampin; CYP3A4; Drug-drug interactions; CYP2D8; Enzyme induction
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Rifampin
• Other Study ID Numbers: 9785-CL-0405; 2012-004841-34 (EUDRACT_NUMBER)