A 2-Part Study to Assess Potential Metabolism-Based Drug-Drug Interactions of E2006 When Coadministered With Itraconazole, Rifampin, Midazolam, or Bupropion

This study will be a single center, open-label, drug-drug interaction study in healthy male and female subjects. The study will consist of 2 parts. In Part A, the effects of steady-state dosing of a strong CYP3A inhibitor (itraconazole) or inducer (rifampin) on the pharmacokinetics of E2006 and metabolites will be assessed. Approximately 30 subjects will be sequentially assigned to 1 of 2 treatment groups to receive itraconazole or rifampin in equal numbers (approximately 15 subjects per group). The itraconazole treatment group will be fully enrolled before enrollment is initiated for the rifampin treatment group. In Part B, the effects of steady-state dosing of E2006 on the pharmacokinetics of midazolam, a substrate of CYP3A, plus bupropion, a substrate of CYP2B6, will be assessed in approximately 24 subjects. The 2 study parts can be conducted in parallel.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: E2006; Drug: rifampin 600 mg; Drug: itraconazole 200 mg; Drug: midazolam 2 mg with bupropion 75 mg

• Study Type: Interventional
• Enrollment (Actual): 106
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Austin, Texas, United States, 78744
      • PPD Development LLC

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria

Subjects must meet all of the following criteria to be included in this study:

1. Healthy males or females, ages 18 to 55 years
2. Body mass index greater than 18 and less than or equal to 32 kg/m2 at Screening
3. All females must be of nonchildbearing potential
4. Males who are not abstinent or have undergone a successful vasectomy, who are partners of women of childbearing potential must use, or their partners must use, a highly effective method of contraception
5. Are willing and able to comply with all aspects of the protocol
6. Provide written informed consent

Exclusion Criteria

Subjects who meet any of the following criteria will be excluded from this study:

1. Any subject that has a known history of malaria or has traveled to a country with known malarial risk (ie, is designated as "high" or "moderate" risk country according to the list available at http://www.cdc.gov/malaria) within the last year
2. Subjects with a history of bowel resection, any malabsorptive disorder, severe gastroparesis, or any gastrointestinal procedure for the purpose of weight loss (including LAP-BANDTM), which would slow gastric emptying and potentially affect PK profiles of E2006
3. Subjects with a known history of clinically significant drug or food allergies
4. Subjects who experienced a weight loss or gain of greater than 10% between Screening and prior to dosing
5. Subjects who had a clinically significant illness that required medical treatment within 8 weeks or a clinically significant infection within 4 weeks of dosing
6. Subjects with any clinically abnormal symptom or organ impairment found in medical history, symptoms or signs, vital sign measurements, electrocardiogram (ECG) findings, or laboratory test results that require medical treatment found in medical history or at screening and baseline
7. Subjects known to be positive for human immunodeficiency virus, or subjects who have positive hepatitis B or hepatitis C screening test results
8. Subjects who have a history of drug or alcohol dependency or abuse (as defined by The Diagnostic and Statistical Manual of Mental Disorders V criteria) within approximately 2 years prior to Screening, or who have a positive urine drug test results at Screening or Baseline
9. Subjects who received blood products within 4 weeks, donated blood within 8 weeks, or donated plasma within 1 week of dosing
10. Subjects who used hormonal replacement therapy within 3 months prior to dosing
11. Subjects who used any drugs, over-the-counter (OTC) medications, nutritional supplements (eg, products containing St John's wort), excessive doses of vitamins (in the opinion of the principal investigator), herbal preparations, or foods or beverages known to modulate CYP (eg, CYP3A4) or transporters within 4 weeks prior to dosing, or who are unwilling to abstain from using these during the study
12. Subjects who engaged in intense physical activity within 1 week prior to Baseline (eg, weight training)
13. Subjects who smoke or have used tobacco or nicotine-containing products within 3 months prior to dosing
14. Subjects who habitually consume more than 400-mg caffeine per day
15. Subjects who participated (received investigational product) in another clinical trial less than 1 month (or 5 elimination half-lives of the investigational product) prior to dosing or who are currently enrolled in another clinical trial

16. Subjects with a disease that may influence the outcome of the study, such as psychiatric disorders and disorders of the gastrointestinal tract, liver, kidney, respiratory system, endocrine system, hematological system, neurological system, or cardiovascular system, or subjects who have a congenital abnormality in metabolism, or subjects who have any condition that would make him or her, in the opinion of the investigator, unsuitable for the study or who, in the opinion of the investigator, are not likely to complete the study for any reason

    Restrictions on concomitant medications, food and beverages:

17. Prescription drugs are prohibited within 4 weeks of dosing and OTC medications within 2 weeks prior to dosing and until the Termination Visit
18. Smoking or use of tobacco or nicotine-containing products is prohibited within 4 weeks prior to dosing and until Termination Visit
19. Intake of caffeinated beverages or food is prohibited 72 hours prior to dosing and throughout the entire study
20. Intake of nutritional supplements, juice, and herbal preparations or other foods or beverages that may affect the various drug metabolizing enzymes and transporters (eg, alcohol, grapefruit, grapefruit juice, grapefruit-containing beverages, apple or orange juice, vegetables from the mustard green family [eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard] and charbroiled meats) is prohibited within 2 weeks prior to dosing until the Termination Visit

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: E2006 Part A; E2006 10-mg tablets alone and in combination with rifampin 600 mg or itraconazole 200 mg	Drug: E2006; Drug: rifampin 600 mg; Drug: itraconazole 200 mg
Experimental: E2006 Part B; E2006 10-mg tablets alone and in combination with midazolam 2 mg plus bupropion 75 mg	Drug: E2006; Drug: midazolam 2 mg with bupropion 75 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of E2006 and its major metabolites, M4, M9, and M10 (Part A), and midazolam, bupropion, and the hydroxylated metabolite of bupropion (Part B): AUC(0-t)	Area under the concentration-time curve from zero time to time of last quantifiable concentration	Approximately 56 Days for Part A; Approximately 42 Days for Part B
Pharmacokinetics of E2006 and its major metabolites, M4, M9, and M10 (Part A), and midazolam, bupropion, and the hydroxylated metabolite of bupropion (Part B): AUC(0-inf)	Area under the concentration-time curve from zero time extrapolated to infinite time	Approximately 56 Days for Part A; Approximately 42 Days for Part B
Pharmacokinetics of E2006 and its major metabolites, M4, M9, and M10 (Part A), and midazolam, bupropion, and the hydroxylated metabolite of bupropion (Part B): Cmax	Maximum observed concentration	Approximately 56 Days for Part A; Approximately 42 Days for Part B

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of E2006 and its major metabolites, M4, M9, and M10 (Part A), and midazolam, bupropion, and the hydroxylated metabolite of bupropion (Part B): tmax	Time at which the highest drug concentration occurs	Approximately 56 Days for Part A; Approximately 42 Days for Part B
Pharmacokinetics of E2006: AUC(0-8h)	Area under the concentration-time curve from time zero time to 8 hours after dosing (E2006 only)	Approximately 56 Days for Part A; Approximately 42 Days for Part B
Pharmacokinetics of E2006: AUC(0-24h)	Area under the concentration-time curve from time zero time to 24 hours after dosing (E2006 only)	Approximately 56 Days for Part A; Approximately 42 Days for Part B
Pharmacokinetics of E2006 and its major metabolites, M4, M9, and M10 (Part A), and midazolam, bupropion, and the hydroxylated metabolite of bupropion (Part B): AUC(0-72h)	Area under the concentration-time curve from zero time to time 72 hours after dosing	Approximately 56 Days for Part A; Approximately 42 Days for Part B
Pharmacokinetics of E2006 and its major metabolites, M4, M9, and M10 (Part A), and midazolam, bupropion, and the hydroxylated metabolite of bupropion (Part B): t1/2	Terminal elimination phase half-life	Approximately 56 Days for Part A; Approximately 42 Days for Part B
Pharmacokinetics of E2006 and its major metabolites, M4, M9, and M10 (Part A), and midazolam, bupropion, and the hydroxylated metabolite of bupropion (Part B): CL/F	Apparent total clearance after extravascular administration	Approximately 56 Days for Part A; Approximately 42 Days for Part B
Pharmacokinetics of E2006 and its major metabolites, M4, M9, and M10 (Part A), and midazolam, bupropion, and the hydroxylated metabolite of bupropion (Part B): AUC(0-inf), metabolite ratio	Ratio of S,S-hydroxybupropion to S-buproprion	Approximately 56 Days for Part A; Approximately 42 Days for Part B

Collaborators and Investigators

• Sponsor: Eisai Inc.

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: March 10, 2014
• First Submitted That Met QC Criteria: March 11, 2014
• First Posted (Estimate): March 13, 2014

Study Record Updates

• Last Update Posted (Estimate): November 3, 2015
• Last Update Submitted That Met QC Criteria: November 2, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: Healthy; Metabolism; Drug-Drug Interactions
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Bacterial Agents; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Hormone Antagonists; Cytochrome P-450 Enzyme Inducers; Antifungal Agents; Steroid Synthesis Inhibitors; Cytochrome P-450 CYP3A Inducers; Dopamine Uptake Inhibitors; Antitubercular Agents; 14-alpha Demethylase Inhibitors; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Midazolam; Bupropion; Rifampin; Itraconazole
• Other Study ID Numbers: E2006-A001-004