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A Single and Repeat Dose PK/PD Study to Characterise Biomarker Response in Healthy Subjects Treated With Azithromycin

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01416350
First received: June 23, 2011
Last updated: August 23, 2012
Last verified: March 2012
History of Changes
  Purpose

This is a two part protocol (Parts A and B) in healthy volunteers evaluating the pharmacokinetics/ pharmacodynamics (PK/PD) of azithromycin to investigate the usefulness of various biomarkers (e.g., Interleukin-10 (IL-10), Granulocyte macrophage colony-stimulating factor (GM-CSF), mature dendritic cell (MDC), with and without ex vivo lipopolysaccharide (LPS) stimulation) as markers of macrolide anti-inflammatory activity.

Part A is a randomized, open-label parallel group study evaluating PK/PD of a single azithromycin dose of 250 or 1000 mg. Data from Part A will be used to assess the dose resulting in induction/inhibition of various ex vivo biomarkers relative to a 250 mg dose of azithromycin (the clinical dose used in treatment of neutrophil-induced inflammatory conditions). This information will guide the range of doses to be studied in a first time in humans (FTIH) study of a new chemical entity.

Part B is a repeat dose study treating subjects with Azithromycin (250 mg every other day for 3 weeks), the dose approximates that used in the treatment of chronic neutrophil related inflammatory conditions. This information will provide insight into whether the biomarker effects change over time on repeat dosing and any potential differences observed between single and repeat doses.


Condition Intervention
Autoimmune Diseases
 Drug: Azithromycin - 250 mg
Drug: Azithromycin - 1000 mg
Drug: Azithromycin - 250 mg every other day for 3 weeks

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: A Single and Repeat Dose Pharmacokinetics/ Pharmacodynamics (PK/PD) Study to Characterise theBiomarker Response in Healthy Subjects Treated With the AntiinflammatoryMacrolide Azithromycin

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • PK/PD modelling of the time course of concentrations and inhibition/induction of relevant biomarkers including the concentration resulting in 50% induction or inhibition (IC50) [ Time Frame: For Part A Day 1 to 15 ] [ Designated as safety issue: No ]
    Parameters from PK/PD modelling of the time course of concentrations and inhibition/induction of relevant ex vivo biomarkers (e.g., MDC, GM-CSF and IL-10 with varying levels of LPS stimulation) including the IC50 along with distribution parameters (e.g., kin and kout).

  • Maximum inhibition/induction of relevant biomarkers and timing of this maximum [ Time Frame: For Part A Day 1 to 15 ] [ Designated as safety issue: No ]
    Maximum inhibition/induction of relevant ex vivo biomarkers (e.g., MDC, GM-CSF and IL-10) and timing of this maximum


Secondary Outcome Measures:
  • Biomarker:Clinical Dose Ratio for each relevant biomarkers [ Time Frame: For Part B Day 1 to 35 ] [ Designated as safety issue: No ]
    Biomarker:Clinical Dose Ratio (dose which would result in maximum observed concentration (Cmax) above the concentration resulting in 80% induction or inhibition (IC80) in ≥75% of patients divided by clinical dose of 250 mg) for each relevant ex vivo biomarkers.

  • Observed maximum inhibition/induction and its coefficient of variation (CV) [ Time Frame: For Part B Day 1 to 35 ] [ Designated as safety issue: No ]
    For each relevant biomarker, the observed maximum inhibition/induction and its coefficient of variation (CV).


Enrollment: 20
Study Start Date: March 2011
Study Completion Date: May 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Part A - randomized, open-label parallel group
Part A is a randomized, open-label parallel group study evaluating PK/PD of a single azithromycin dose of 250 or 1000 mg. Data from Part A will be used to assess the dose resulting in induction/inhibition of various ex vivo biomarkers relative to a 250 mg dose of azithromycin (the clinical dose used in treatment of neutrophil-induced inflammatory conditions). This information will guide the range of doses to be studied in a FTIH study of a new chemical entity.
 Drug: Azithromycin - 250 mg
Part A - A single azithromycin dose of 250 mg.
Drug: Azithromycin - 1000 mg
Part A - A single azithromycin dose of 1000 mg.
Part B - repeat dose group
Part B is a repeat dose study treating subjects with Azithromycin (250 mg every other day for 3 weeks), the dose approximates that used in the treatment of chronic neutrophil-related inflammatory conditions. This information will provide insight into whether the biomarker effects change over time on repeat dosing and any potential differences observed between single and repeat doses.
 Drug: Azithromycin - 250 mg every other day for 3 weeks
Part B - Repeat dose study treating subjects with Azithromycin (250 mg every other day for 3 weeks), the dose approximates that used in the treatment of chronic neutrophil-related inflammatory conditions.

Detailed Description:

This is a two part protocol (Parts A and B) in healthy volunteers evaluating the pharmacokinetics/ pharmacodynamics (PK/PD) of azithromycin to investigate the usefulness of various biomarkers (e.g., IL-10, GM-CSF, MDC, with and without ex vivo lipopolysaccharide (LPS) stimulation) as markers of macrolide anti-inflammatory activity.

Part A is a randomized, open-label parallel group study evaluating PK/PD of a single azithromycin dose of 250 or 1000 mg. Data from Part A will be used to assess the dose resulting in induction/inhibition of various ex vivo biomarkers relative to a 250 mg dose of azithromycin (the clinical dose used in treatment of neutrophil-induced inflammatory conditions). This information will guide the range of doses to be studied in a FTIH study of a new chemical entity.

Part B is a repeat dose study treating subjects with Azithromycin (250 mg every other day for 3 weeks), the dose approximates that used in the treatment of chronic neutrophil related inflammatory conditions. This information will provide insight into whether the biomarker effects change over time on repeat dosing and any potential differences observed between single and repeat doses.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population

Healthy volunteers

Criteria

Inclusion Criteria:

  • Male or female between 18 and 65 years of age inclusive
  • Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy
  • Child-bearing potential and agrees to use one of the contraception methods
  • Body weight ≥ 50 kg and body mass index (BMI) within the range 18.5 - 30 kg/m2 (inclusive)
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions
  • Single QT duration corrected for heart rate by Bazett's formula (QTcB) < 450 msec.

Exclusion Criteria:

  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities
  • A positive pre-study drug/alcohol screen
  • A positive test for HIV antibody
  • History of regular alcohol consumption within 6 months of the study
  • The subject has participated in a clinical trial and has received an investigational product within the 3 months
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day
  • Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements
  • History of sensitivity to any of the study medications, or erythromycin, any macrolide or ketolide antibiotic
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period
  • The subject has donated blood in the 3 months prior to the study
  • Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing
  • Lactating females
  • Unwillingness or inability to follow the procedures outlined in the protocol
  • Subject is mentally or legally incapacitated
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01416350

Locations
United Kingdom
GSK Investigational Site
London, United Kingdom, NW10 7EW
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01416350     History of Changes
Other Study ID Numbers: 115360
Study First Received: June 23, 2011
Last Updated: August 23, 2012
Health Authority: United Kingdom: Research Ethics Committee

Additional relevant MeSH terms:
Autoimmune Diseases
Immune System Diseases
Azithromycin
Anti-Bacterial Agents
 Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 16, 2013