This study is a methodology study to evaluate a microdose strategy for DDI which will be
useful in the evaluation of the backup compounds for GSK706769, as well as possibly other
assets. The safety, tolerability and pharmacokinetics will be evaluated in healthy adult
subjects. This will be an open-label fixed-sequence 2-period study in healthy male
volunteers after oral administration of [14C]-GSK706769 alone and in the presence of
Ketoconazole.
Inclusion Criteria:
- Males 18-50 years of age inclusive, at the time of signing the informed consent.
- AST, 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%).
- Signed written informed consent prior to beginning study-related procedures.
Subjects must understand the aims, investigational procedures and possible
consequences of the study and must be able to understand and comply with protocol
requirements, instructions and protocol-stated restrictions.
- Healthy as determined by a responsible and experienced 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 and the Medical Monitor agree that the finding is unlikely to
introduce additional risk factors and will not interfere with the study procedures.
- Male subjects must agree to use one of the contraception methods listed in Section
8. 1. This criterion must be followed from the time of the first dose of study
medication until 7 days post-last dose.
- Body weight greater than or equal to 50 kg (110 pounds) and body mass index (BMI)
between 19 and 35 kg/m2 (inclusive)
- Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form.
- Average QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch
Block.
Exclusion Criteria:
- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
result within 3 months of screening
- Current or chronic history of liver disease, or known hepatic or biliary
abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- A positive pre-study drug/alcohol screen.
- A positive test for HIV antibody.
- History of regular alcohol consumption within 6 months of the study defined in the
protocol.
- 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
dosing day.
- Use of prescription or non-prescription drugs, including vitamins, herbal and dietary
supplements (including St John's Wort) within 14 days or 5 half-lives (whichever is
longer) prior to the first dose of study medication, unless in the opinion of the
Investigator and Medical Monitor the medication will not interfere with the study
procedures or compromise subject safety.
- History of sensitivity to any of the study medications (including Ketoconazole), or
components thereof or a history of drug or other allergy that, in the opinion of the
investigator or Medical Monitor, contraindicates their participation.
- Where participation in the study would result in donation of blood or blood products
in excess of 500 mL within a 56 day period.
- Any medical or surgical conditions that might significantly interfere with the
gastrointestinal absorption, distribution, metabolism, or excretion of the study
drugs (eg, gastrectomy).
- Subjects who have been involved in a 14C human research study within the previous 12
months.
- Unwillingness or inability to follow the procedures outlined in the protocol.
- Subject is mentally or legally incapacitated.
- History of sensitivity to heparin or heparin-induced thrombocytopenia.
- Consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or
pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior
to the first dose of study medication until the completion of the study.
