Validation Study of Multiple Probe Compounds for Drug Interaction Evaluation

NCT00964106 | Completed Phase 1

• 1 other identifier: 112684
• Study Type: interventional
• Target: 87
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to identify and validate a probe cocktail for use in future 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 combination of the 7 drugs given together as a cocktail. 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.

Conditions

Drug Interactions

Keywords

inducer; midazolam; inhibitor; rosiglitazone; dextromethorphan; caffeine; cocktail; pioglitazone; omeprazole; CYP; rosuvastatin; probe drug; drug interaction; flurbiprofen

Outcome Measures

Primary Outcomes (1)

• Pharmacokinetic parameters

  Plasma AUC (0-inf) of probe and metabolite (where applicable) when administered alone, in combination with other probes/inhibitors

  life of study

Secondary Outcomes (1)

• To assess the safety and tolerability of co-administration of probe drugs

  life of study

Study Arms (2)

Probe drugs

EXPERIMENTAL

Caffeine 100 mg CYP1A2 Pioglitazone 15 mg CYP2C8 Flurbiprofen 40 mg CYP2C9 Omeprazole 20 mg CYP2C19 Dextromethorphan 45 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

Drug: Caffeine; Drug: Rosiglitazone; Drug: Flurbiprofen; Drug: Omeprazole; Drug: Dextromethorphan; Drug: Midazolam; Drug: Rosuvastatin

Default Inhibitors

EXPERIMENTAL

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

Drug: Ketoconazole; Drug: Fluconazole; Drug: Rifampin

Interventions

Caffeine DRUG

Caffeine dosed at 100 mg as probe for CYP1A2 pathway

Probe drugs

Rosiglitazone DRUG

Dosed at 4 mg as probe for CYP2C8 pathway

Probe drugs

Flurbiprofen DRUG

Dosed at 40 mg, probe for CYP2C9 pathway

Probe drugs

Omeprazole DRUG

Dosed at 20 mg, probe for CYP2C19 pathway

Probe drugs

Dextromethorphan DRUG

Dosed at 30 mg, probe for CYP2D6 pathway

Probe drugs

Midazolam DRUG

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

Probe drugs

Rosuvastatin DRUG

Dosed at 10 mg, probe drug for OATP1B1 pathway

Probe drugs

Ketoconazole DRUG

Dosed at 400 mg once-daily Day 1 through Day 9, inhibitor of CYP3A4

Default Inhibitors

Fluconazole DRUG

Dosed at 400 mg x 1 dose on day 1, 200 mg once daily on days 2 through 9, inhibitor of CYP2C9 pathway

Default Inhibitors

Rifampin DRUG

Dosed at 600 mg x 1 dose on Day 1 and Day 8, inhibitor of OATP1B1 pathway

Default Inhibitors

Eligibility Criteria

• Age: 20 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy as determined by a responsible physician
• 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
• Able to understand and comply with protocol requirements

You may not qualify if:

• 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. 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 and foods, or alcohol-containing beverages within 72 hours prior to dosing
• Consumption of the following foods or drinks within 72 hrs prior to dosing : 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
• Urinary cotinine levels indicative of current smoking or history of regular use of tobacco- or nicotine-containing products within two months prior to screening.
• 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
• 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, pioglitazone, midazolam, rosuvastatin, flurbiprofen, ketoconazole, fluconazole, rifampin, quinidine, gemfibrozil, and fluvoxamine.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (2)

GSK Investigational Site

Busan, 614-735, South Korea

Location

GSK Investigational Site

Seoul, 110-744, South Korea

Location

Related Links

• Results for study 112684 can be found on the GSK Clinical Study Register.

MeSH Terms

Interventions

Caffeine; Rosiglitazone; Flurbiprofen; Omeprazole; Dextromethorphan; Midazolam; Rosuvastatin Calcium; Ketoconazole; Fluconazole; Rifampin

Intervention Hierarchy (Ancestors)

Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Propionates; Acids, Acyclic; Carboxylic Acids; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Pyridines; Benzimidazoles; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Benzodiazepines; Benzazepines; Sulfonamides; Amides; Fluorobenzenes; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Sulfones; Pyrimidines; Piperazines; Triazoles; Rifamycins; Lactams, Macrocyclic; Macrocyclic Compounds

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 23, 2009
• First Posted: August 24, 2009
• Study Start: August 26, 2009
• Primary Completion: August 29, 2011
• Study Completion: August 29, 2011
• Last Updated: January 4, 2018

Record last verified: 2018-01

Data Sharing

• IPD Sharing: Will share

Locations

KR (2)