This study is meant to assess potential inhibitory effects of GSK376501 on CYP450 isoenzymes
3A4, 2C8, 2C9. subjects will receive probe compounds and systemic levels of these substrates
will be compared pre and post dosing of GSK376501.
- Healthy as determined by a qualified physician, based on a medical evaluation
including medical history, physical examination, laboratory tests and cardiac
monitoring. A subject with a clinical abnormality or laboratory parameters outside the
reference range for the population being studied may be included only if the
Investigator considers that the finding is unlikely to introduce additional risk
factors and will not interfere with the study procedures.
- Male or female between 18 and 55 years of age.
- A female subject is eligible to participate if she is of non-childbearing potential,
defined as: a. pre-menopausal females with a documented tubal ligation or
hysterectomy; or b. postmenopausal defined as 12 months of spontaneous amenorrhea [in
questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH)
> 40 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is confirmatory].
- Body weight ≥ 50 kg and BMI within the range 19 - 30 kg/m2 (inclusive).
- Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form.
- Demonstrates an average QTc interval < 450 msec (or < 480 msec in subjects with bundle
branch block), an average PR interval < 200 msec, and a QRS duration < 110msec (manual
or machine read) at screening or baseline
- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
result within 3 months of screening.
- A positive test for HIV antibody.
- The subject has participated in a clinical trial and has received an investigational
product within the following time period prior to the first dosing day in the current
study: 30 days, 5 half-lives or twice the duration of the biological effect of the
investigational product (whichever is longer).
- Exposure to more than four new chemical entities within 12 months prior to the first
- Previous exposure to GSK376501.
- Unwillingness or inability to follow the procedures outlined in the protocol.
- Demonstrates symptomatic or asymptomatic arrhythmia of any clinical significance
- The subject has a positive pre-study drug/alcohol screen and is unwilling to abstain
from 72 hours prior to dose until follow-up. A minimum list of drugs that will be
screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and
- Urinary cotinine levels indicative of smoking or history or use of tobacco or
nicotine-containing products within 6 months prior to screening.
- Has a history of alcohol abuse or dependence within 12 months prior to the study.
Alcohol abuse is defined as an average consumption of greater than 7 drinks per week
for women or greater than 14 drinks per week for men. One alcohol drink is defined as
the equivalent of 12 g of alcohol as follows: 5 oz/150 ml wine, 12 oz (360 ml) beer or
1.5 oz (45 ml) of 80 proof distilled spirits.
- Use of prescription or non-prescription drugs, including vitamins, herbal and dietary
supplements (including St John's Wort, kava, ephedra [ma huang], gingko biloba, DHEA,
vohimbe, saw palmetto, ginseng, red yeast rice) within 7 days (or 14 days if the drug
is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the
first dose of study medication and is unwilling to abstain from use of these
medications until the last pharmacokinetic or pharmacodynamic sample has been
collected, unless in the opinion of the Investigator and GSK Medical Monitor the
medication will not interfere with the study procedures or compromise subject safety.
- Use of caffeine- or xanthine-containing products for 24 hours prior to dose until the
last pharmacokinetic sample has been collected.
- Consumption of any food or any beverage containing (alcohol, grapefruit or
- grapefruit juice, apple or orange juice, Seville oranges, vegetables from the mustard
green family [e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussels
sprouts, mustard] and charbroiled meats). from 7 days prior to the first dose of study
- Use of acetaminophen within 48 hours of the first dose and is unable or unwilling to
discontinue use of acetaminophen until the last pharmacokinetic sample has been
- Use of aspirin, aspirin-containing compounds, salicylates or nonsteroidal
anti-inflammatory drugs (NSAIDs) within 48 hours days of the first dose and is
unwilling to abstain from use of these medications until the last pharmacokinetic
sample has been collected.
- Use of liquid antacids (e.g. Maalox, Mylanta, Amphogel, milk of magnesia) or chewable
antacids (e.g. TUMS™) within 48 hours of the first dose and is unwilling to abstain
from use of these medications until the last dose of study medication.
- History of sensitivity to any of the study medications, or components thereof or a
history of drug or other allergy that, in the opinion of the investigator or GSK
Medical Monitor, contraindicates their participation.
- Alkaline phosphatase value higher than 1.5 times the upper limit of normal at
screening or at baseline.
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT), direct (conjugated)
bilirubin, or CPK values higher than 1.25 times upper limit of normal at screening or
- Fasting triglyceride level > 400 mg/dL (4.52 mmol/L) at screening or at baseline.
Triglyceride levels within a 10% margin above this level will be considered on a
- Donation of blood or blood products in excess of 500 mL within a 56 day period.
- History of sensitivity to heparin or heparin-induced thrombocytopenia.
- History of or current congestive heart failure (NYHA Class I-IV symptoms)
- History of thyroid dysfunction or an abnormal thyroid function test as assessed by TSH