Effect of GSK376501 on CYP450 Activity in Healthy Adult Subjects

NCT00615212 | Completed Phase 1

• 1 other identifier: DIX110825
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

This study is meant to assess potential inhibitory effects of GSK376501 on CYP450 isoenzymes 3A4, 2C8, 2C9. subjects will receive probe compounds and systemic levels of these substrates will be compared pre and post dosing of GSK376501.

Conditions

Diabetes Mellitus, Type 2

Keywords

Healthy Subjects,; Cytochrome P450 isoenzymes,; Repeat Dose; GSK376501,

Outcome Measures

Primary Outcomes (3)

• drug plasma levels midazolam:

  Days 1 & 11

• drug plasma levels rosiglitazone:

  Days 2 & 12

• drug plasma levels flurbiprofen:

  Days 3 & 13

Secondary Outcomes (4)

• adverse reactions,changes in laboratory values,changes in vital signs, & ECG changes:

  Days 1-13

• drug plasma levels GSK376501:

  Days 4-13

• Safety and tolerability during dosing with GSK376501, alone and in combination with the various probe substrates.

  Up to Day 24

• Daily predose trough GSK376501 plasma concentrations when administered alone for 7 days (Days 4-13).

  for 7 days (Days 4-13).

Study Arms (7)

Subjects receiving midazolam

ACTIVE COMPARATOR

Eligible subjects will receive midazolam oral syrup with a dose of 5 milligrams on Day 1.

Drug: Midazolam

Subjects receiving rosiglitazone

ACTIVE COMPARATOR

Eligible subjects will receive rosiglitazone oral tablet with a dose of 4 milligrams on Day 2.

Drug: Rosiglitazone

Subjects receiving flurbiprofen

ACTIVE COMPARATOR

Eligible subjects will receive flurbiprofen oral tablet with a dose of 50 milligrams on Day

Drug: Flurbiprofen

Subjects receiving GSK376501

EXPERIMENTAL

Eligible subjects will receive GSK376501 oral tablet with a dose of 75 milligrams from Day 4 to Day 10.

Drug: GSK376501

Subjects receiving GSK376501+ midazolam

EXPERIMENTAL

Eligible subjects will receive GSK376501 oral tablet with a dose of 75 milligrams along with midazolam oral tablet of 5 milligrams on Day 11.

Drug: GSK376501; Drug: Midazolam

Subjects receiving GSK376501 + rosiglitazone

EXPERIMENTAL

Eligible subjects will receive GSK376501 oral tablet with a dose of 75 milligrams along with rosiglitazone oarl tablet of 4 milligrams on Day 12.

Drug: GSK376501; Drug: Rosiglitazone

Subjects receiving GSK376501 + flurbiprofen

EXPERIMENTAL

Eligible subjects will receive GSK376501 oral tablet with a dose of 75 milligrams along with flurbiprofen oral tablet of 50 milligrams on Day 13.

Drug: GSK376501; Drug: Flurbiprofen

Interventions

GSK376501 DRUG

GSK376501 oral tablet will be available with dosing strengths of 75 milligrams administered once daily. Biconvex, It will be a round, white film-coated tablets with both plain sides and no identifying markings.

Subjects receiving GSK376501; Subjects receiving GSK376501 + flurbiprofen; Subjects receiving GSK376501 + rosiglitazone; Subjects receiving GSK376501+ midazolam

Midazolam DRUG

Midazolam oral syrup will be available with a dose of 5 milligrams administered once daily. It will be a clear, red to purplish-red, cherry-flavored syrup.

Subjects receiving GSK376501+ midazolam; Subjects receiving midazolam

Rosiglitazone DRUG

Rosiglitazone oral tablet will be available with dosing strengths of 4 milligrams administered once daily. It will be a orange colored tablet debossed with SB on one side and 4 on the other.

Subjects receiving GSK376501 + rosiglitazone; Subjects receiving rosiglitazone

Flurbiprofen DRUG

Rosiglitazone oral tablet will be available with dosing strengths of 50 milligrams administered once daily. It will be a blue, oval, film coated tablet.

Subjects receiving GSK376501 + flurbiprofen; Subjects receiving flurbiprofen

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy as determined by a qualified physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator considers that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
• Male or female between 18 and 55 years of age.
• A female subject is eligible to participate if she is of non-childbearing potential, defined as: a. pre-menopausal females with a documented tubal ligation or hysterectomy; or b. postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/ml and estradiol \< 40 pg/ml (\<140 pmol/L) is confirmatory\].
• Body weight ≥ 50 kg and BMI within the range 19 - 30 kg/m2 (inclusive).
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Demonstrates an average QTc interval \< 450 msec (or \< 480 msec in subjects with bundle branch block), an average PR interval \< 200 msec, and a QRS duration \< 110msec (manual or machine read) at screening or baseline

You may not qualify if:

• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
• A positive test for HIV antibody.
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
• Previous exposure to GSK376501.
• Unwillingness or inability to follow the procedures outlined in the protocol.
• Demonstrates symptomatic or asymptomatic arrhythmia of any clinical significance during screening.
• The subject has a positive pre-study drug/alcohol screen and is unwilling to abstain from 72 hours prior to dose until follow-up. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
• Urinary cotinine levels indicative of smoking or history or use of tobacco or nicotine-containing products within 6 months prior to screening.
• Has a history of alcohol abuse or dependence within 12 months prior to the study. Alcohol abuse is defined as an average consumption of greater than 7 drinks per week for women or greater than 14 drinks per week for men. One alcohol drink is defined as the equivalent of 12 g of alcohol as follows: 5 oz/150 ml wine, 12 oz (360 ml) beer or 1.5 oz (45 ml) of 80 proof distilled spirits.
• Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort, kava, ephedra \[ma huang\], gingko biloba, DHEA, vohimbe, saw palmetto, ginseng, red yeast rice) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication and is unwilling to abstain from use of these medications until the last pharmacokinetic or pharmacodynamic sample has been collected, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
• Use of caffeine- or xanthine-containing products for 24 hours prior to dose until the last pharmacokinetic sample has been collected.
• Consumption of any food or any beverage containing (alcohol, grapefruit or
• grapefruit juice, apple or orange juice, Seville oranges, vegetables from the mustard green family \[e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard\] and charbroiled meats). from 7 days prior to the first dose of study medication.
• Use of acetaminophen within 48 hours of the first dose and is unable or unwilling to discontinue use of acetaminophen until the last pharmacokinetic sample has been collected.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Buffalo, New York, 14202, United States

Location

Related Links

• Results for study DIX110825 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Midazolam; Rosiglitazone; Flurbiprofen

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Propionates; Acids, Acyclic; Carboxylic Acids; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 1, 2008
• First Posted: February 14, 2008
• Study Start: January 2, 2008
• Primary Completion: February 15, 2008
• Study Completion: February 15, 2008
• Last Updated: September 11, 2017

Record last verified: 2017-09

Locations

US (1)