Official Title: “Validation Study of Simultaneous Administration of Multiple Cytochrome P450/Transporter Probes for Drug Interaction Evaluation in Healthy Adult Subjects”

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.

Study Type: Interventional

Study Design: Basic Science, Randomized, Open Label, Crossover Assignment, Pharmacokinetics Study

Study Primary Completion Date: January 2010

The primary purpose of this study is to establish a validated drug cocktail, containing up to 7 probes, for assessing the activity of six drug metabolizing enzymes (CYP 1A2, 2C8, 2C9, 2C19, 2D6, 3A4/5) and the OATP1B1 transporter. In Part 1, the study will determine if there are pharmacokinetic interactions among the probe drugs by comparing the pharmacokinetics of the probe drugs when administered alone and in combination (i.e., as a cocktail). In Part 2, the study will evaluate the quantitative performance of the cocktail by examining the effect of select inhibitors on the pharmacokinetics of respective probe drugs when the probe drugs are administered alone versus when administered in the cocktail.

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.

Intervention(s) in this Clinical Trial

• Drug: Ketoconazole
  • Dosed at 400 mg once-daily Day 1 through Day 9, inhibitor of CYP3A4
• Drug: Fluconazole
  • Dosed at 400 mg x 1 dose on day 1, 200 mg once daily on days 2 through 9, inhibitor of CYP2C9 pathway
• Drug: Rifampin
  • Dosed at 600 mg x 1 dose on Day 1 and Day 8, inhibitor of OATP1B1 pathway
• Drug: Quinidine
  • Dosed at 100 mg x 1 dose on Day 1 and Day 8, inhibitor of CYP2D6 pathway
• Drug: Gemfibrozil
  • Dosed at 600 mg twice daily on Days 1-9, inhibitor of CYP2C8 pathway
• Drug: Fluvoxamine
  • Dosed 50 mg once-daily Days 1-9, inhibitor of CYP2C19 pathway
• Drug: Rosiglitazone
  • Dosed at 4 mg as probe for CYP2C8 pathway
• Drug: Flurbiprofen
  • Dosed at 40 mg, probe for CYP2C9 pathway
• Drug: Omeprazole
  • Dosed at 20 mg, probe for CYP2C19 pathway
• Drug: Caffeine
  • Caffeine dosed at 100 mg as probe for CYP1A2 pathway
• Drug: Dextromethorphan
  • Dosed at 30 mg, probe for CYP2D6 pathway
• Drug: Midazolam
  • Dosed at 3 mg for Part 1, Part 2 cohorts B and C and 1 mg for Part 2 Cohort A, probe drug for CYP3A4/5 pathway
• Drug: Rosuvastatin
  • Dosed at 10 mg, probe drug for OATP1B1 pathway

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Probe drugs
  • Caffeine 100 mg CYP1A2 Rosiglitazone 4 mg CYP2C8 Flurbiprofen 40 mg CYP2C9 Omeprazole 20 mg CYP2C19 Dextromethorphan 30 mg CYP2D6 Midazolam 3 mg (Part 1, Part 2 Cohorts B and C) 1 mg (Part 2 Cohort A) CYP3A4/5 Rosuvastatin 10 mg OATP1B1
• Experimental: Contingency Inhibitors
  • A CYP2D6 Quinidine 100 mg x 1 dose on Day 1 and Day 8 B CYP2C8 Gemfibrozil 600 mg twice-daily Day 1 through Day 9 C CYP2C19 Fluvoxamine 50 mg once-daily Day 1 through Day 9 These inhibitors will only be used if midazolam, flurbiprofen, or rosuvastatin are removed from the cocktail due to a PK interaction observed in Part 1 of the study.
• Experimental: Default Inhibitors
  • A Ketoconazole 400 mg once-daily Day 1 through Day 9 CYP3A4 B Fluconazole 400 mg x1 dose on Day 1 200 mg once-daily Day 2 through Day 9 CYP2C9 C Rifampin 600 mg x1 dose on Day 1 and Day 8 OATP1B1

Primary Measures

• To identify and establish a set of probe drugs which do not have a pharmacokinetic interaction with each other and could be used in future cocktail studies in any combination
  • Time Frame: life of study
    Safety Issue?: No

Secondary Measures

• To assess the safety and tolerability of co-administration of probe drugs
  • Time Frame: life of study
    Safety Issue?: No

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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 20 Years

Maximum Age for this Clinical Trial: 50 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: GlaxoSmithKline

Overall Clinical Trial Officials and Contacts

GSK Clinical Trials Study Director GlaxoSmithKline  

Overall Contact: US GSK Clinical Trials Call Center 877-379-3718 

Information obtained from ClinicalTrials.gov on February 04, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00964106

Study ID Number: 112684

ClinicalTrials.gov Identifier: NCT00964106

Health Authority: South Korea: Food and Drug Administration