The purpose of this study is to identify and validate a probe cocktail for use in future GSK
drug-drug interaction studies. Cytochrome P450 enzymes and transport proteins play
important roles in the disposition of drugs. Changes in the activity of these pathways can
be assessed using probe drugs selected on the basis of their metabolic or transport pathway.
This will be a two part study with the same subjects participating in both parts to
decrease variability in data. The purpose of Part 1 is to identify a set of probe drugs
('cocktail') which do not interact with one another; groups of healthy volunteers will
receive 7 probe drugs individually and as a single combination of the 7 drugs given together
as a cocktail. The pathways which mediate clearance of the selected probe drugs are CYP1A2,
CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP2D6 and OATP1B1. Between Part 1 and 2, there will be a
pharmacokinetic analysis period of approximately 6 weeks when subjects do not have to visit
the clinic. If substantial PK interactions are observed, a conditional Part 1B may be
performed to evaluate a modified cocktail where probes subject to interaction are removed.
Part 2 will assess the performance of the probe cocktail using three known inhibitors
(validation). The inhibitors plus probe cocktail will evaluate the ability of the newly
established cocktail to accurately quantify metabolizing enzyme or transporter inhibition,
representing a fundamental advance in probe cocktail validation and utility for drug
development.
The validation step in Part 2 represents a fundamental advance in cocktail studies, as it
will provide novel data on whether a DDI study utilizing a cocktail approach yields a
quantitatively accurate result compared to a traditional one-probe, one-inhibitor DDI study
design. For example, 'is a similar magnitude of increase in the AUC of midazolam observed
when midazolam alone is given with ketoconazole compared to when a cocktail (containing
midazolam) is given with ketoconazole? ' This study will directly test whether the two
results are similar; if they are similar, then the study will provide substantial support to
advance cocktail studies from a DDI screening tool to a definitive (quantitatively accurate)
study design.
This study aims to establish a standard probe cocktail that can be used for drug-drug
interaction studies, with the intention that any subset of the 7-drug cocktail could be
selected for study with a drug in development (i. e., the cocktail could be streamlined to
contain only the specific pathways affected by the study drug based on in vitro data).
In addition, this study will provide a proof-of-principle evaluation of dried blood spot
technology as a method to measure drug concentrations in blood samples collected from
clinical studies. Results from the drug blood spot analysis will be reported separately by
DMPK. Dried blood spot technology offers advantages in sample volume, preparation, storage,
shipment, and analysis which could translate into improved convenience, reduced blood
volumes, and cost savings if the technique is shown to be suitable for PK analysis of
biological samples.
Inclusion Criteria:
- Healthy as determined by a responsible physician, based on a medical evaluation
including medical history, physical examination, laboratory tests and cardiac
monitoring.
- Subjects are not poor metabolizers based on genotyping for the major CYP2C9, 2C19,
2D6 alleles
- Male or female between 20 and 50 years of age at the time of screening, inclusive.
- A female subject is eligible to participate if she is of Non-childbearing potential
or postmenopausal
- Body weight greater than or equal to 45 kg and BMI within the range 18. 5 to 24. 9
kg/m2 (inclusive).
- QTc < 450 msec
- Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form.
- Able to understand and comply with protocol requirements, instructions and
protocol-stated restrictions.
Exclusion Criteria:
- As a result of the medical interview, physical examination, or screening
investigations, the Investigator considers the subject unfit for the study.
- Use of prescription or non-prescription drugs, including vitamins, herbal and dietary
supplements within 7 days (14 days if the drug is a potential enzyme inducer, such as
Panaz ginseng, Gingko biloba or St. John's Wort [Hypericum perforatum]) or 5
half-lives (whichever is longer) prior to the first dose of study medication in each
Part of the study and during each active part of the study (e. g., Part 1 and Part 2),
unless in the opinion of the Investigator and sponsor the medication will not
interfere with the study procedures or compromise subject safety. Herbal medications
include, but are not limited to: traditional Chinese, Korean and Japanese medicines,
Panaz ginseng, Gingko biloba or St John's wort (Hypericum perforatum) or any
Traditional Chinese herbal medicines (TCM) South Asian Ayurvedic medicine,
Traditional Korean Medicines and Japanese Kampo.
- Use of caffeine- or theobromine-containing beverages (e. g., coffee, tea, certain
colas, green tea and oolong tea, Yerba Mate, Guarana, and South American cocoa) and
foods (e. g., chocolate), or alcohol-containing beverages within 72 hours prior to
dosing in each Part of the study and during each active part of the study (e. g., Part
1 and Part 2).
- Consumption of the following foods or drinks within 72 hrs prior to dosing in each
Part of the study and during each active part of the study (e. g., Part 1 and Part 2):
red wine, Seville oranges, grapefruits, pommelos, cruciferous vegetables (e. g.,
broccoli, Brussels sprouts, cabbage, celery), char-grilled meats, grapefruit juice.
- The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs
that will be screened for include amphetamines, barbiturates, cocaine, opiates,
cannabinoids and benzodiazepines.
- Urinary cotinine levels indicative of current smoking or history of regular use of
tobacco- or nicotine-containing products within two months prior to screening. This
includes chewing tobacco, Gutka, hand-rolled tobacco cigarettes, Biddis, cigars, and
Snuff.
- A positive Hepatitis B surface antigen or positive Hepatitis C antibody at screening.
- A positive test for HIV antibody
- History of regular alcohol consumption within 6 months of the study
- 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, five half-lives or twice the duration of the biological effect of the
investigational product (whichever is longer).
- Systolic blood pressure outside the range of 80 to 140 mmHg, without antihypertensive
therapy and no history of hypertension or diastolic blood pressure outside the range
of 60 to 85 mmHg, or heart rate outside the range of 50 to 100 beats per minute (bpm)
for female and 45 to 100 beats per minute (bpm) for male subjects. Blood pressure
and heart rate should be taken after 10 minutes of rest.
- History of syncope or vaso-vagal attacks.
- Pre-existing condition interfering with normal gastrointestinal anatomy or motility,
hepatic or renal function, that could interfere with the absorption, metabolism, or
excretion of the study drugs.
- Exposure to more than four new chemical entities within 12 months prior to the first
dosing day.
- Has a known intolerance or hypersensitivity to aspirin, NSAIDS, or benzodiazepines,
or a known intolerance to the active and/or inactive ingredients in omeprazole,
dextromethorphan, caffeine, rosiglitazone, midazolam, rosuvastatin, flurbiprofen,
ketoconazole, fluconazole, rifampin, quinidine, gemfibrozil, and fluvoxamine.
- Has any condition or symptom contraindicated for administration of the probe
compounds or inhibitors as follows: omeprazole (hypersensitivity, gastric ulcer with
possible malignant tumor), dextromethorphan (hypersensitivity to dextromethorphan,
co-administration with monoamine oxidase inhibitors), caffeine (hypersensitivity to
caffeine), rosiglitazone (heart disease, edema), midazolam (narrow angle glaucoma),
rosuvastatin (liver disease, LFT elevations), flurbiprofen (digestant ulcer),
ketoconazole (LFT elevations), fluconazole (LFT elevations), rifampin (porphyria,
LFT elevations), quinidine (heart conduction abnormalities - e. g., A-V block;
junctional rhythm), gemfibrozil (hepatic dysfunction, renal dysfunction, gallbladder
disease) and fluvoxamine (use of monoamine oxidase (MAO) inhibitors within 14 days of
fluvoxamine administration). The Investigator should also reference the product
information of each drug administered in the study.
- History of sensitivity to heparin or heparin-induced thrombocytopenia (if heparin is
used to maintain the patency of an intravenous cannula).
- Where participation in the study would result in donation of blood or blood products
in excess of 500 mL within a 56 day period.
- EGG abnormalities
- Pregnant females or lactating females.
