Ondansetron, also known as Zofran, is a marketed compound used for the prevention of nausea
and vomiting. This study, called a thorough QT study, will characterize the effects of a
single intravenous (IV) dose of ondansetron on cardiac repolarization as compared to
placebo. Moxifloxacin, a commercially available antibiotic known to cause a mild QT
prolongation, will be used as a positive control and will be given orally. The cardiac
repolarization will be measured by taking consecutive ECGs on a recording device known as a
Holter monitor and measuring the QT interval at specified times. In addition, blood samples
will also be taken at specified times and will be used to measure the amount of study
medication in the body.
Inclusion Criteria:
- Healthy adult men and women, non-smokers between 18 and 45 years of age inclusive, at
the time of signing the informed consent. Every effort will be made to enrol an
approximately equal number of males and females.
- Signed and dated written informed consent prior to admission to the study, which
includes compliance with the requirements and restrictions listed in the consent
form.
- Healthy as judged by a responsible physician, with no clinically significant
abnormality identified on the medical or laboratory evaluation performed at
Screening, 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 with the approval of the GSK medical monitor.
- ALT, alkaline phosphatase and bilirubin less than or equal to 1. 5xULN (isolated
bilirubin >1. 5xULN is acceptable if bilirubin is fractionated and direct bilirubin
<35%).
- 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 either has had a hysterectomy or has had a bilateral
oophorectomy (ovariectomy) or is post-menopausal defined as being amenorrhoeic for
greater than or equal to 1 year with an appropriate clinical profile, e. g., age
appropriate, history of vasomotor symptoms. Follicle-stimulating hormone (FSH) must
be greater than or equal to 40 mIU/mL to confirm the post-menopausal state.
If a female is of child-bearing potential, has a negative serum pregnancy test at
Screening, and agrees to or has undergone one of the following: Complete abstinence from
sexual intercourse from 2 weeks prior to administration of the study drug until completion
of the follow-up procedures, or, bilateral tubal ligation, or have a vasectomized partner
or use an intrauterine device with published data showing that expected failure rate is
less than 1% per year (e. g., GynaeFix) from 2 weeks prior to administration of study drug
until completion of the follow-up procedures, or, use double-barrier method [condom or
occlusive cap (diaphragm or cervical/vault caps) used with spermicidal
foam/gel/cream/suppository].
- Body Mass Index (BMI)* in the range of 19 - 30 kg/m2 (inclusive). *[BMI = weight
[kg]/(height [m])2]
Exclusion Criteria:
- Cardiac conduction abnormalities denoted by any of the following at screening:
QTc interval > 450 msec; PR interval > 240 msec or less than or equal to 110 msec;
evidence of second- or third-degree atrioventricular (AV) block; pathological Q-waves
(defined as Q-wave > 40 msec or depth greater than 0. 4 - 0. 5 mV); evidence of ventricular
pre-excitation; electrocardiographic evidence of complete left bundle branch block, right
bundle branch block (RBBB), incomplete LBBB; intraventricular conduction delay with QRS
duration > 120 msec; bradycardia as defined by sinus rate < 50 bpm.
- Any history of myocardial infarction, syncope, long-QT syndrome, cardiac arrhythmias,
or a history of uncontrolled hypertension or unstable heart disease within the 6
months prior to the screening visit, or a family history of long-QT syndrome or a
family history of sudden death.
- Family history of heart attack or stroke at age less than or equal to 60 years.
- Levels of potassium, magnesium, and calcium outside the normal reference range at
screening.
- Clinically significant serum chemistry and complete blood count parameters outside
the normal reference range at screening.
- Positive for HIV antibody, hepatitis B virus S-antigen (HbSAg) or hepatitis C (Hep C)
virus antibody at screening.
- Current or chronic history of liver disease, or known hepatic or biliary
abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- History of alcohol/drug abuse or dependence within 12 months of the study.
- History of regular alcohol consumption within 6 months of the study defined as: an
average weekly intake of >14 drinks for males or >7 drinks for females. One drink is
equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine
or 1. 5 ounces (45 mL) of 80 proof distilled spirits.
- A positive pre-study urine test for drugs of abuse including alcohol at screening or
prior to the start of dosing. A minimum list of drugs that will be screened for
includes amphetamines, barbiturates, cocaine, opiates, cannabinoids, benzodiazepines,
and cotinine. Subjects will be re-screened at each treatment period.
- 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 4 new chemical entities within 12 months prior to the first
dosing day.
- Use of prescription or non-prescription drugs, including vitamins, herbal and dietary
supplements (including St John's Wort) 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 GSK medical
monitor the medication will not interfere with the study procedures or compromise
subject safety.
- 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.
- The subject has donated blood or blood products in excess of 500 mL within a 56 day
period.
- Pregnant females as determined by positive serum hCG test at screening.
- Consumption of aspirin, aspirin-containing compounds, salicylates or nonsteroidal
anti-inflammatory agents (NSAIDs) within 14 days of the study start and until the end
of the follow-up visit. Acetaminophen (less than or equal to 2 g/day) will be
permitted during the study for analgesia.
- Subject has consumed liquid antacids (e. g., Maalox, Mylanta, Amphojel, Milk of
Magnesia) or chewable antacids (e. g., TUMS™) within 48 hours of the first dose of
study medication, and throughout the duration of study drug administration.
- History of sensitivity to moxifloxacin or any member of the quinolone class of
antimicrobial agents, or history of drug or other allergy that, in the opinion of the
physician responsible, contraindicates their participation. If use of an IV cannula
with heparinized flush is anticipated for PK draws, then hypersensitivity to heparin
is also exclusionary.
- Urinary cotinine levels indicative of smoking or history or regular use of tobacco-
or nicotine-containing products within 6 months prior to screening.
- Consumption of red wine, seville oranges, grapefruit or grapefruit juice, pomelos,
exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the
first dose of study medication.
