Validation Study of Multiple Probe Compounds for Drug Interaction Evaluation
Summary
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.
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.
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.
Study Design
Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Basic Science
Conditions
Healthy Volunteer
Intervention
Ketoconazole, Fluconazole, Rifampin, Quinidine, Gemfibrozil, Fluvoxamine, Rosiglitazone, Flurbiprofen, Omeprazole, Caffeine, Dextromethorphan, Midazolam, Rosuvastatin
Location
GSK Investigational Site
Busan
Korea, Republic of
614-735
Status
Recruiting
Source
GlaxoSmithKline
Results (where available)
Links
- Source: http://clinicaltrials.gov/show/NCT00964106
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Gemfibrozil
A lipid-regulating agent that lowers elevated serum lipids primarily by decreasing serum triglycerides with a variable reduction in total cholesterol. These decreases occur primarily in the VLDL fraction and less frequently in the LDL fraction. Gemfibrozil increases HDL subfractions HDL2 and HDL3 as well as apolipoproteins A-I and A-II. Its mechanism of action has not been definitely established.
Rifampin
A semisynthetic antibiotic produced from Streptomyces mediterranei. It has a broad antibacterial spectrum, including activity against several forms of Mycobacterium. In susceptible organisms it inhibits DNA-dependent RNA polymerase activity by forming a stable complex with the enzyme. It thus suppresses the initiation of RNA synthesis. Rifampin is bactericidal, and acts on both intracellular and extracellular organisms. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p1160)
Quinidine
An optical isomer of quinine, extracted from the bark of the Cinchona tree and similar plant species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. It prolongs cellular action potential, and decreases automaticity. Quinidine also blocks muscarinic and alpha-adrenergic neurotransmission.
Ketoconazole
Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients.
Flurbiprofen
An anti-inflammatory analgesic and antipyretic of the phenylalkynoic acid series. It has been shown to reduce bone resorption in periodontal disease by inhibiting CARBONIC ANHYDRASE.
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PubMed Articles
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Effects of Rifampin and Ketoconazole on the Pharmacokinetics of Nilotinib in Healthy Participants.
Nilotinib (Tasigna), an orally bioavailable second-generation BCR-ABL tyrosine kinase inhibitor, is approved for use in patients with chronic myeloid leukemia in chronic phase and accelerated phase wh...
