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| Sponsor: | GlaxoSmithKline |
|---|---|
| Information provided by: | GlaxoSmithKline |
| ClinicalTrials.gov Identifier: | NCT00964106 |
Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Drug Interactions Healthy Volunteer |
Drug: Caffeine Drug: Rosiglitazone Drug: Flurbiprofen Drug: Omeprazole Drug: Dextromethorphan Drug: Midazolam Drug: Rosuvastatin Drug: Ketoconazole Drug: Fluconazole Drug: Rifampin Drug: Pioglitazone |
Phase I |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Pharmacokinetics Study Intervention Model: Crossover Assignment Masking: Open Label Primary Purpose: Basic Science |
| Official Title: | Validation Study of Simultaneous Administration of Multiple Cytochrome P450/Transporter Probes for Drug Interaction Evaluation in Healthy Adult Subjects |
| Enrollment: | 100 |
| Study Start Date: | August 2009 |
| Study Completion Date: | August 2011 |
| Primary Completion Date: | August 2011 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Probe drugs
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
Caffeine dosed at 100 mg as probe for CYP1A2 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: 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
Drug: Pioglitazone
Dosed at 15 mg, probe drug for CYP2C8 pathway
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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
|
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
|
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.
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.
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.
Eligibility| Ages Eligible for Study: | 20 Years to 50 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
Exclusion Criteria:
Contacts and Locations| Korea, Republic of | |
| GSK Investigational Site | |
| Busan, Korea, Republic of, 614-735 | |
| GSK Investigational Site | |
| Seoul, Korea, Republic of, 110-744 | |
| Study Director: | GSK Clinical Trials | GlaxoSmithKline |
More Information
| Responsible Party: | Cheri Hudson; Clinical Disclosure Advisor, GSK Clinical Disclosure |
| ClinicalTrials.gov Identifier: | NCT00964106 History of Changes |
| Other Study ID Numbers: | 112684 |
| Study First Received: | July 23, 2009 |
| Last Updated: | August 25, 2011 |
| Health Authority: | South Korea: Food and Drug Administration |
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inducer midazolam inhibitor rosiglitazone dextromethorphan caffeine cocktail |
pioglitazone omeprazole CYP rosuvastatin probe drug drug interaction flurbiprofen |
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Caffeine Dextromethorphan Midazolam Flurbiprofen Fluconazole Ketoconazole Omeprazole Rifampin Rosuvastatin Pioglitazone Rosiglitazone Central Nervous System Stimulants Physiological Effects of Drugs Pharmacologic Actions Central Nervous System Agents |
Therapeutic Uses Phosphodiesterase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Purinergic P1 Receptor Antagonists Purinergic Antagonists Purinergic Agents Neurotransmitter Agents Excitatory Amino Acid Antagonists Excitatory Amino Acid Agents Antitussive Agents Respiratory System Agents Adjuvants, Anesthesia Anti-Anxiety Agents Tranquilizing Agents |