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Effect of GSK376501 on CYP450 Activity in Healthy Adult Subjects

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00615212
First received: February 1, 2008
Last updated: September 8, 2017
Last verified: September 2017
  Purpose
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.

Condition Intervention Phase
Diabetes Mellitus, Type 2 Drug: GSK376501 Drug: Midazolam Drug: Rosiglitazone Drug: Flurbiprofen Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single Center, Single Sequence, Open-Label, Repeat-Dose Study to Investigate the Effect of GSK376501 on Hepatic Cytochrome P450 Activity in Healthy Adult Subjects

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • drug plasma levels midazolam: [ Time Frame: Days 1 & 11 ]
  • drug plasma levels rosiglitazone: [ Time Frame: Days 2 & 12 ]
  • drug plasma levels flurbiprofen: [ Time Frame: Days 3 & 13 ]

Secondary Outcome Measures:
  • adverse reactions,changes in laboratory values,changes in vital signs, & ECG changes: [ Time Frame: Days 1-13 ]
  • drug plasma levels GSK376501: [ Time Frame: Days 4-13 ]
  • Safety and tolerability during dosing with GSK376501, alone and in combination with the various probe substrates. [ Time Frame: Up to Day 24 ]
  • Daily predose trough GSK376501 plasma concentrations when administered alone for 7 days (Days 4-13). [ Time Frame: for 7 days (Days 4-13). ]

Enrollment: 23
Actual Study Start Date: January 2, 2008
Study Completion Date: February 15, 2008
Primary Completion Date: February 15, 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Subjects receiving midazolam
Eligible subjects will receive midazolam oral syrup with a dose of 5 milligrams on Day 1.
Drug: Midazolam
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.
Active Comparator: Subjects receiving rosiglitazone
Eligible subjects will receive rosiglitazone oral tablet with a dose of 4 milligrams on Day 2.
Drug: Rosiglitazone
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.
Active Comparator: Subjects receiving flurbiprofen
Eligible subjects will receive flurbiprofen oral tablet with a dose of 50 milligrams on Day
Drug: Flurbiprofen
Rosiglitazone oral tablet will be available with dosing strengths of 50 milligrams administered once daily. It will be a blue, oval, film coated tablet.
Experimental: Subjects receiving GSK376501
Eligible subjects will receive GSK376501 oral tablet with a dose of 75 milligrams from Day 4 to Day 10.
Drug: GSK376501
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.
Experimental: Subjects receiving GSK376501+ midazolam
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
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.
Drug: Midazolam
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.
Experimental: Subjects receiving GSK376501 + rosiglitazone
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
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.
Drug: Rosiglitazone
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.
Experimental: Subjects receiving GSK376501 + flurbiprofen
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
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.
Drug: Flurbiprofen
Rosiglitazone oral tablet will be available with dosing strengths of 50 milligrams administered once daily. It will be a blue, oval, film coated tablet.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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.
  • Use of aspirin, aspirin-containing compounds, salicylates or nonsteroidal anti-inflammatory drugs (NSAIDs) within 48 hours days of the first dose and is unwilling to abstain from use of these medications until the last pharmacokinetic sample has been collected.
  • Use of liquid antacids (e.g. Maalox, Mylanta, Amphogel, milk of magnesia) or chewable antacids (e.g. TUMS™) within 48 hours of the first dose and is unwilling to abstain from use of these medications until the last dose of study medication.
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
  • Alkaline phosphatase value higher than 1.5 times the upper limit of normal at screening or at baseline.
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), direct (conjugated) bilirubin, or CPK values higher than 1.25 times upper limit of normal at screening or at baseline.
  • Fasting triglyceride level > 400 mg/dL (4.52 mmol/L) at screening or at baseline. Triglyceride levels within a 10% margin above this level will be considered on a case-by-case basis.
  • Donation of blood or blood products in excess of 500 mL within a 56 day period.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • History of or current congestive heart failure (NYHA Class I-IV symptoms)
  • History of thyroid dysfunction or an abnormal thyroid function test as assessed by TSH as screening.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00615212

Locations
United States, New York
GSK Investigational Site
Buffalo, New York, United States, 14202
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Additional Information:
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00615212     History of Changes
Other Study ID Numbers: DIX110825
Study First Received: February 1, 2008
Last Updated: September 8, 2017

Keywords provided by GlaxoSmithKline:
Healthy Subjects,
Cytochrome P450 isoenzymes,
Repeat Dose
GSK376501,

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Midazolam
Rosiglitazone
Flurbiprofen
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on September 20, 2017