Study to Evaluate the Effect of Naltrexone and Bupropion Combination on the Pharmacokinetics of Metformin in Healthy Participants

A Phase 1, Open-Label, Sequential Design Study to Evaluate the Potential Effect of Multiple Oral Doses of Extended-Release Combination of Naltrexone and Bupropion on the Pharmacokinetics of a Single Oral Dose of Metformin in Healthy Subjects

The purpose of this study is to determine the effect of multiple oral doses of naltrexone/bupropion on the pharmacokinetics (PK) of a single oral dose of metformin.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: Naltrexone/Bupropion; Drug: Metformin

Detailed Description

The drug being tested in this study is naltrexone HCl and bupropion HCl Extended- Release fixed dose combination (NB) . This study will evaluate the potential effect of multiple oral doses of extended-release combination of naltrexone/bupropion on the PK of a single oral dose of metformin in healthy participants with normal renal function (defined as creatinine clearance [CrCl] greater than equal to [>=] 90 milliliter per minute [mL/min]/1.73 meter square [m^2]).

The study will enroll approximately 30 participants. Participants will receive:

Metformin 850 mg as a single dose alone and in combination with multiple doses of Naltrexone/Bupropion Naltrexone 8 mg/Bupropion 90 mg + Naltrexone 16 mg/Bupropion 180 mg as multiple doses alone and in combination with a single dose of metformin

All participants will be asked to take 1 tablet of metformin in the morning on Day 1 and Day 14, 1 tablet of naltrexone/bupropion twice daily from Day 3 through Day 5, and 2 tablets of naltrexone/bupropion twice daily from Day 6 through Day 15.

This single center trial will be conducted in the United States. The overall time to participate in this study is 73 days. Participants will be admitted on Day -1 (check in) and remain confined to the clinic until Day 16 and will be contacted by telephone 30 (±2) days after last dose of study drug for a follow-up assessment. Serial blood samples will be collected for PK assessments. Safety will be monitored throughout the study.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Is a healthy male or female.
2. Is aged 18 to 55 years, inclusive, at signing of informed consent and first dose of study drug.
3. Weighs at least 50 kilogram (kg) and has a body mass index (BMI) of 18.0 to 40.0 kilogram per square meter (kg/m^2), inclusive, at Screening.
4. Has normal renal function (defined as CrCl >=90 mL/min/1.73 m^2) at Screening and Check-in (Day -1).
5. A female subject of childbearing potential* who is sexually active with a nonsterilized* male partner agrees to use adequate contraception* from signing of informed consent throughout the duration of the study and for 12 weeks after the last dose of study drug.

Exclusion Criteria:

1. Has known hypersensitivity to metformin, bupropion, naltrexone, or any component of the formulations.
2. Has history of seizure of any etiology, or of predisposition to seizures.
3. Has history of bulimia.
4. Has history of anorexia nervosa.
5. Has resting heart rate outside the normal range of 45 to 100 beats per minutes at Screening or Check-in (Day -1) and confirmed by a repeat measurement approximately 30 minutes following the initial measurement.
6. Has orthostatic blood pressure >=25 millimeter of mercury (mm Hg) at Screening or Check-in (Day -1) and confirmed by a repeat measurement approximately 30 minutes following the initial measurement.
7. Has sustained supine systolic blood pressure >=140 mm Hg or less than equal to (<=) 90 mm Hg or a diastolic blood pressure >=90 mm Hg or <=50 mm Hg at Screening or Check-in (Day -1) and confirmed by a repeat measurement approximately 30 minutes following the initial measurement.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin + Naltrexone/Bupropion; Metformin (850 mg, immediate release tablet, orally, once on Day 1 and Day 14) naltrexone/bupropion (8/90 mg/mg, extended-release tablets, orally, twice daily from Day 3 through Day 5 and 16/180 mg/mg, twice daily from Day 6 through Day 15.	Drug: Naltrexone/Bupropion; Naltrexone/Bupropion extended-release tablets.; Drug: Metformin; Metformin immediate-release tablet.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Cmax: Maximum Observed Plasma Concentration for Metformin Following a Single Dose of Metformin Administered Alone	Day 1: predose and at multiple timepoints (up to 48 hours) post-dose
Cmax: Maximum Observed Plasma Concentration of Metformin Following a Single Dose of Metformin and multiple Doses of naltrexone/bupropion	Day 14: predose and at multiple timepoints (up to 48 hours) post-dose
AUC(0-inf): Area Under the Plasma Concentration-time Curve from Time 0 to Infinity of Metformin Following a Single Dose of Metformin Administered Alone	Day 1: predose and at multiple timepoints (up to 48 hours) post-dose
AUC(0-inf): Area Under the Plasma Concentration-time Curve from Time 0 to Infinity of Metformin Following a Single Dose of Metformin and Multiple Doses of naltrexone/bupropion	Day 14: predose and at multiple timepoints (up to 48 hours) post-dose

Secondary Outcome Measures

Outcome Measure	Time Frame
Cmax: Maximum Observed Plasma Concentration of bupropion, naltrexone and their metabolites (6beta-naltrexol, Bupropion, Hydroxybupropion, Threohydrobupropion, and Erythrohydrobupropion) following multiple doses of NB alone	Day 13 predose and at multiple timepoints (up to 12 hours) post-dose
Cmax: Maximum Observed Plasma Concentration of bupropion, naltrexone and their metabolites following multiple doses of naltrexone/bupropion and a single dose of metformin	Day 14: predose and at multiple timepoints (up to 12 hours) post-dose
AUC(0-tau): Area Under the Plasma Concentration-time Curve during a dosing interval for upropion, naltrexone and their metabolites (6beta-naltrexol, Bupropion, Hydroxybupropion, Threohydrobupropion, and Erythrohydrobupropion)	Day 13: predose and at multiple timepoints (up to 12 hours) post-dose for naltrexone/buprop alone, Day 14: predose and at multiple timepoints (up to 12 hours) post-dose, Day 14: predose and at multiple timepoints (up to 48 hours) post-dose
• Percentage of Participants who Experience at Least one Treatment Emergent Adverse Event (TEAE)	Day 1 upt to Day 45

Collaborators and Investigators

• Sponsor: Orexigen Therapeutics, Inc

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): August 1, 2016

Study Registration Dates

• First Submitted: April 18, 2016
• First Submitted That Met QC Criteria: April 18, 2016
• First Posted (Estimate): April 20, 2016

Study Record Updates

• Last Update Posted (Estimate): September 29, 2016
• Last Update Submitted That Met QC Criteria: September 27, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Sensory System Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Narcotic Antagonists; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Alcohol Deterrents; Dopamine Uptake Inhibitors; Naltrexone; Bupropion; Metformin
• Other Study ID Numbers: NaltrexBuprop-1004; U1111-1166-8630 (Other Identifier: WHO)