Validation Study of Multiple Probe Compounds for Drug Interaction Evaluation
Condition: Drug Interactions
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Caffeine; Rosiglitazone; Flurbiprofen; Omeprazole; Dextromethorphan; Midazolam; Rosuvastatin; Ketoconazole; Fluconazole; Rifampin; Rosiglitazone
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Caffeine dosed at 100 mg as probe for CYP1A2 pathway; Dosed at 4 mg as probe for CYP2C8 pathway; Dosed at 40 mg, probe for CYP2C9 pathway; Dosed at 20 mg, probe for CYP2C19 pathway; Dosed at 30 mg, probe for CYP2D6 pathway; 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; Dosed at 10 mg, probe drug for OATP1B1 pathway; Dosed at 400 mg once-daily Day 1 through Day 9, inhibitor of CYP3A4; Dosed at 400 mg x 1 dose on day 1, 200 mg once daily on days 2 through 9, inhibitor of CYP2C9 pathway; Dosed at 600 mg x 1 dose on Day 1 and Day 8, inhibitor of OATP1B1 pathway; Dosed at 15 mg, probe drug for CYP2C8 pathway
Intervention MeSH terms: Rosiglitazone; Rifampin; Fluconazole; Ketoconazole; Flurbiprofen; Midazolam; Dextromethorphan; Caffeine; Omeprazole; Rosuvastatin Calcium
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: inducer; midazolam; inhibitor; rosiglitazone; dextromethorphan; caffeine; cocktail; pioglitazone; omeprazole; CYP; rosuvastatin; probe drug; drug interaction; flurbiprofen