The purpose of this research study is to look at concentrations of GSK189075, WELLBUTRIN SR
and active metabolic products in blood samples when doses of both drugs are taken by mouth.
Doses are either taken alone or together. The results will help to determine if doses of
GSK189075 and WELLBUTRIN SR can be safely taken together.
INCLUSION CRITERIA:
- Healthy male subjects aged 18 to 55 years inclusive.
- Body Mass Index (BMI) is between 19-35kg/m2 (inclusive), with a minimum body weight of
45kg.
- Subject must read and write at a comprehension level that is sufficient to provide
written informed consent, and be able to understand and comply with protocol
requirements, instructions and protocol-stated restrictions.
- Subject has provided informed consent to participate in the study as indicated by
providing a signed and dated written informed consent form prior to the initiation of
any study procedures.
EXCLUSION CRITERIA:
- General
- Presence of any clinically relevant abnormality identified on the screening
medical assessment, laboratory examination or 12-lead ECG, or any other medical
condition or circumstance making the volunteer unsuitable for participation in
the study. These include any unstable medical disorder; disorders that would
interfere with the action, absorption, distribution, metabolism, or excretion of
bupropion or GSK189075; disorders which may pose a safety concern or interfere
with the accurate assessment of safety or efficacy.
- Laboratory
- Clinically significant abnormalities at Screening including:
- Systolic blood pressure outside the range of 90 - 140 mmHg, diastolic blood
pressure outside the range of 50 - 90 mmHg, and pulse rate at rest > 100 and < 45
bpm.
- Positive tests for hepatitis B surface antigen, hepatitis C antibodies, and HIV.
- Positive cotinine, drug and/or alcohol test.
- Significant ECG abnormalities are defined as follows:
- Parameter Range
- Heart Rate < 40 and >100 bpm
- PR Interval <120 and > 220 ms
- QRS duration < 70 and >120 ms
- QTC Interval (Bazett) > 450 ms
- ALT, alkaline phosphatase, or total bilirubin ³ 1. 5 times the upper limits of
normal (Note: Subjects with an increased total bilirubin may enter the study only
if direct bilirubin is within normal limits).
- Fasting triglycerides >400 mg/dL (>11. 3 mmol/L).
- Clinically significant abnormalities of T3 and TSH.
- Serum creatinine clearance <60ml/min (estimated from serum creatinine (SCr) and
demographic data using the MDRD calculation):
- A validated web-based calculator is found at:
- http://nephron. com/cgi-bin/MDRDSIdefault. cgi
- To calculate estimated GFR (mL/min/1. 73m2) manually:
- = 186 x (SCr in mg/dL)-1. 154 x (age)-0. 203 x (0. 742 if female) x (1. 210 if
African-American)
- = exp(5. 228-1. 154 x ln (SCr)-0. 203x ln(age)-(0. 299 if female) + (0. 192 if African
American))
- Any other clinically significant laboratory abnormality as determined by the
Principal Investigator in consultation with the GSK Medical Monitor.
- Central Nervous System
- Current diagnosis or a previous history of mania, psychosis, major depression, or
other major psychiatric disorder.
- Current or past history of seizure disorder or brain injury (traumatic or
disease-related); or any condition which, in the opinion of the investigator,
predisposes to seizure; those treated with other medications or treatment regimes
that lower seizure threshold; those undergoing abrupt discontinuation of alcohol
or sedatives (including benzodiazepines or benzodiazepine-like agents).
- Note: A single childhood febrile seizure is not exclusionary.
- History or current diagnosis of anorexia nervosa or bulimia.
- Subjects who, in the investigator's judgement, pose a homicidal or suicidal risk,
have ever made a suicide attempt, or have ever been homicidal.
- Hepatic and Gastrointestinal systems
- History of hepatic disease or known hepatic or biliary abnormalities, (with the
exception of previously documented diagnosis of Gilbert's syndrome) and/or a
history of biliary or gastrointestinal disorder, which might affect absorption,
distribution, metabolism, or excretion of drugs (except appendectomy or
cholecystectomy more than 12 weeks prior to the study).
- Endocrine system
- Untreated or unstable thyroid disease. Subjects taking thyroid medications must
be on a stable dosing regimen for at least 4 weeks prior to the first dose of
study drug until completion of the Follow-up visit.
- Cardiac system
- Subject has a history of clinically significant cardiac rhythm disorder or QTc
interval ³450 milliseconds at Screening.
- Subject has history of ischemic heart disease, including stable/unstable angina
or acute myocardial infarction.
- Uncontrolled hypertension with systolic blood pressure >140mm Hg and diastolic
blood pressure >90mm Hg.
Drugs and Alcohol
- Subject has a history of alcohol abuse or an average weekly intake of greater than 21
units per week (one unit = 1 glass of wine = 1 measure of spirits = ½ pint of beer).
- Unwilling or unable to abstain from the use of illicit drugs and adhere to other
protocol-stated restrictions while participating in the study.
- Use of tobacco in any form (smoking cigarettes, cigars, and/or pipes, or chewing
tobacco-containing products), for 4 weeks prior to Screening until completion of the
Follow-up visit.
- Unwilling or unable to abstain from the use of prescription or non-prescription drugs,
vitamins, or dietary/herbal supplements within 1 week prior to the first dose of study
drug until completion of the Follow-up visit.
- Subject is currently using medications that may alter gastric/small bowel motility,
result in diarrhea, or bind concomitant medications. For example, but not limited to:
erythromycin, antacids, prokinetic agents and cholestyramine.
- Subject has a history of drug or other allergy that, in the opinion of the Principal
Investigator, contraindicates their participation in this study.
• Concomitant medications usage that includes:
- Use of agents that are known to inhibit or induce cytochrome P450 enzymes within 14
days prior to the first dose of study medication , including grapefruit-containing
products and St. John's Wort.
- Use of bupropion hydrochloride or GSK189075 within the last 6 months prior to
Screening.
- Use of anti-depressant medication for clinically significant depression.
- Use of prescription or non-prescription drugs, including vitamins, herbal and dietary
supplements within 7 days prior to the first dose in Treatment Period 1, unless in the
opinion of the Investigator and Sponsor the medication will not interfere with the
study procedures or compromise subject safety.
- Note: Occasional use of acetaminophen and ibuprofen according to directions
provided in the product label may be acceptable during the study, at the
discretion of the Principal Investigator. Acetaminophen will be limited to doses
up to 2 grams/day and ibuprofen at doses up to 1. 2 grams/day.
- Drug hypersensitivity
- History of hypersensitivity to WELLBUTRIN SR, ZYBAN, GSK189075 or any of their
constituents or closely related compounds.
- History of sensitivity to heparin or heparin-induced thrombocytopenia.
- Other
- Past treatment with a new molecular entity (investigational drug) or any other trial
during the previous 30 days, or 5 half-lives, whichever is longer. A new molecular
entity is defined as any compound not in Phase 3. (The washout period of 30 days is
counted from the last dose of study drug in the previous study until the first dose of
study drug).
- Participation in the study would result in subject's donation of blood in excess of
500mL within a 56-day period.
