Advertisement

Topics

Validation Study of Multiple Probe Compounds for Drug Interaction Evaluation

2014-08-27 03:19:50 | BioPortfolio

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)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:19:50-0400

Clinical Trials [437 Associated Clinical Trials listed on BioPortfolio]

Drug-drug Interaction Study Between EDP-305, Fluconazole and Quinidine in Healthy Volunteers

This is a non-randomized, 2-part, open-label, drug-drug interaction (DDI) study to evaluate the effect of concomitant administration of fluconazole or quinidine on the pharmacokinetics and...

A Comparison of Fluconazole and Ketoconazole in the Treatment of Fungal Infections of the Throat in Patients With Weakened Immune Systems

To compare the safety, tolerance, and effectiveness of fluconazole and ketoconazole in the treatment of candidal esophagitis in immunocompromised patients.

Interplay Between Organic Anion Transporting Polypeptide (OATP) Transporters Transporters and CYP2C9 in Glyburide Pharmacokinetics (PK)

The purpose of this study is to investigate if the drugs rifampin and fluconazole when given together increase the concentrations in the body of the oral diabetes medication glyburide.

Study to Assess Pharmacokinetic Drug-Drug Interaction Between Avatrombopag When Co-Administered With Fluconazole, Itraconazole, or Rifampin in Healthy Subjects

The purpose of this study is to determine the effects of concomitant administration with fluconazole, itraconazole, and rifampin on the pharmacokinetics (PK) of a single 20-mg dose of avat...

Drug Drug Interaction Study Evaluating the Effect of Fluvoxamine or Fluconazole on PK and Safety of PF-04965842.

A Phase 1, Open Label, Parallel-Cohort, Randomized, Fixed Sequence Study To Evaluate The Pharmacokinetic Drug Drug Interaction Between PF-04965842 and Fkuvoxamine (cohort 1) or Fluconazole...

PubMed Articles [207 Associated PubMed Articles listed on BioPortfolio]

Procognitive effects of fluvoxamine: preliminary data.

To identify and investigate procognitive effects of fluvoxamine.

Effect of oral fluconazole 1200 mg/day on QT interval in African adults with HIV-associated cryptococcal meningitis.

: We assessed the effect of fluconazole 1200 mg/day on QT interval in cryptococcal meningitis patients. Mean QTc change from baseline to day 7 was 10.1ms (IQR: -28 to 46) in the fluconazole treatmen...

HO-1 upregulation by rosiglitazone via ROS-dependent Nrf2-ARE axis or PPARγattenuates lipopolysaccharide-mediated lung inflammation.

Heme oxygenase-1 (HO-1) is induced by thiazolidinediones including rosiglitazone and exerts anti-inflammatory effects in various models. However, the molecular mechanisms underlying rosiglitazone-indu...

Oral flurbiprofen spray for mucosal graft harvesting at the palatal area: A randomized placebo-controlled study.

Flurbiprofen which is a non-steroidal anti-inflammatory drug (NSAID), has been safely used for the control of postoperative patient's morbidity after periodontal plastic surgeries requiring palatal gr...

Fluconazole resistance is not a predictor of poor outcome in patients with cryptococcosis.

Cryptococcus isolates with high MICs to fluconazole are increasingly reported and a potential clinical impact has been advocated. However, there are different methods to evaluate fluconazole MICs and ...

Medical and Biotech [MESH] Definitions

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.

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.

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)

Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients.

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.

More From BioPortfolio on "Validation Study of Multiple Probe Compounds for Drug Interaction Evaluation"

Advertisement
Quick Search
Advertisement
Advertisement

 

Relevant Topics

Pharmacy
Pharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs. The scope of...

Drug Discovery
Clinical Approvals Clinical Trials Drug Approvals Drug Delivery Drug Discovery Generics Drugs Prescription Drugs In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are dis...

Nutrition
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...


Searches Linking to this Trial