To determine safety, tolerability and pharmacokinetics of GSK1349572
- The subject is healthy.
- Healthy as judged by a responsible physician with no clinically significant
abnormality identified on the medical or laboratory evaluation, including 12-lead
ECG. A subject with a clinical abnormality or laboratory parameters outside the
reference range for this age group may be included only if the Investigator considers
that the finding will not introduce additional risk factors and will not interfere
with the study procedures.
- The subject is ≥18 and ≤55 years of age.
- The subject is male or female.
- A female is eligible to enter and participate in this study if she is of
non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
including any female who:
- Has had a hysterectomy or
- Has had a bilateral oophorectomy (removal of the ovaries) or
- Has had a bilateral tubal ligation or
- Is post-menopausal (a demonstration of total cessation of menses for ≥ 1 year
from the date of screening visit). A follicle stimulating hormone (FSH) level
will be performed to confirm a post-menopausal state. For this study FSH levels
≥ 40mIU/mL are consistent with menopause. If a subject is on estrogen
replacement and menopausal status is questionable, estrogen replacement should
be discontinued for 2 weeks and then the subject rescreened, as estrogen
replacement can suppress FSH.
- A male is eligible to enter and participate in the study if he is surgically sterile
OR if he either agrees to abstain from sexual intercourse with a female partner or
agrees to use a condom/spermicide, in addition to having his female partner use
another form of contraception, such as an intrauterine device (IUD), occlusive cap
(diaphragm or cervical/vault cap) with spermicide, oral contraceptives, injectable
progesterone, subdermal implants, female condom, contraceptive patch, or
contraceptive vaginal ring, or has had a tubal ligation or hysterectomy. These
criteria must be followed from the time of the first dose of study medication until
14 days after the last dose of study medication.
- Body weight ≥ 50 kg (110 lbs.) for men and ≥ 45 kg (99 lbs.) for women and body mass
index (BMI) between 18.5-29.9 kg/m2 inclusive.
- A signed and dated written informed consent is obtained from the subject prior to
- The subject is able to understand and comply with protocol requirements, instructions
and protocol-stated restrictions and is likely to complete the study as planned.
- As a result of the medical interview, physical examination, or screening
investigations, the Investigator considers the subject unfit for the study.
- The subject's systolic blood pressure is outside the range of 90-140mmHg, or
diastolic blood pressure is outside the range of 45-90mmHg or heart rate is outside
the range of 50-100bpm for female subjects or 45-100 bpm for male subjects.
- History/evidence of symptomatic or asymptomatic arrhythmia, angina/ischemia, coronary
artery bypass grafting surgery or percutaneous transluminal coronary angioplasty or
any clinically significant cardiac disease.
- History/evidence of clinically significant pulmonary disease.
- Has a positive pre-study Hepatitis B surface antigen; positive hepatitis C (HCV)
antibody or detectable HCV ribonucleic acid (RNA); or positive HIV-1 antibody result.
- Has a history of regular alcohol consumption averaging >7 drinks/week for women or
>14 drinks/week for men (1 drink (12 g alcohol) = 5 ounces (150 ml) of wine or 12
ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof distilled spirits) within 6
months of the screening visit.
- Unwilling to abstain from alcohol for 48 hours prior to the start of dosing until
collection of the final pharmacokinetic sample during each treatment period.
- Has a history of regular use of tobacco- or nicotine-containing products within 3
months of the screening visit.
- The subject has a positive pre-study drug and/or alcohol screen.
- Unwilling to refrain from the use of illicit drugs and adhere to other
protocol-stated restrictions while participating in the study.
- The subject has received an investigational drug or participated in any other
research trial within 30 days or 5 half-lives, or twice the duration of the
biological effect of any drug (whichever is longer) prior to the first dose of
current study medication.
- Participation in the study would result in donation of blood in excess of 500 mL
within a 56 day period.
- History or presence of allergy or intolerance to the study drug or its components or
drugs of its class, or a history of drug or other allergy that, in the opinion of the
physician responsible, contraindicates their participation. In addition, if heparin
is used during PK sampling, subjects with a history of sensitivity to heparin or
heparin-induced thrombocytopenia should not be enrolled.
- Use of prescription or non-prescription drugs, including antacids, vitamins, herbal
and dietary supplements (including St John's Wort and iron supplements) 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, unless in the opinion of the
Investigator and sponsor the medication will not interfere with the study procedures
or compromise subject safety.
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, or
serum creatinine values greater than the upper limit of normal. A single repeat is
allowed for eligibility determination.
- Subjects with a pre-existing condition interfering with normal gastrointestinal
anatomy or motility, hepatic and/or renal function, that could interfere with the
absorption, metabolism, and/or excretion of the study drugs. Subjects with a history
of cholecystectomy should be excluded.
- History of significant renal or hepatic diseases.
- History of Gilbert's syndrome.
- Exclusion Criteria for 24-Hour Screening Holter:
- Any symptomatic arrhythmia (except isolated extra systoles).
- Sustained cardiac arrhythmias (such as atrial fibrillation or flutter,
supraventricular tachycardia (≥10 consecutive beats), complete heart block).
- Non-sustained or sustained ventricular tachycardia (defined as ≥ 3 consecutive
ventricular ectopic beats).
- Any conduction abnormality (including but not specific to left or right
incomplete or complete bundle branch block, atrioventricular (AV) block [2nd
degree or higher], WPW syndrome etc.).
- Sinus Pauses > 3 seconds.
- 300 or more supraventricular ectopic beats in 24 hours.
- 250 or more ventricular ectopic beats in 24 hours.
- Evidence of previous myocardial infarction (Does not include ST segment changes
associated with repolarization).
- Any conduction abnormality (including but not specific to left or right incomplete or
complete bundle branch block, AV block [2nd degree or higher], WPW syndrome).
- Sinus Pauses > 3 seconds.
- Any significant arrhythmia which, in the opinion of the principal investigator and
GSK medical monitor, will interfere with the safety for the individual subject.
- Non-sustained or sustained ventricular tachycardia (≥3 consecutive ventricular