NCT00964106

Validation Study of Multiple Probe Compounds for Drug Interaction Evaluation

An Open-label Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Cytochrome P450 Probe Drugs in Healthy Adult Subjects

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 87 (actual)
• Sponsor: GlaxoSmithKline · Industry
• Sex: All
• Age: 20 Years – 50 Years
• Healthy volunteers: Accepted

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.

Detailed description

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.

Conditions

• Drug Interactions

Interventions

Type	Name	Description
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	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	Rosiglitazone	Dosed at 15 mg, probe drug for CYP2C8 pathway

Timeline

• Start date: 2009-08-26
• Primary completion: 2011-08-29
• Completion: 2011-08-29
• First posted: 2009-08-24
• Last updated: 2018-01-04

Locations

2 sites across 1 country: South Korea