GSK2190915A - Bioavailability Study
Condition: Asthma
Study type: Interventional
Phase: Phase 1

Summary: 
      GSK2190915 is a high affinity 5-lipoxygenase-activating protein (FLAP) inhibitor that reduces
      inflammation in cells.

      This study will evaluate three capsule and two tablet formulations to select the optimal
      formulation for further development. Safety will be assessed through clinical laboratory
      testing, 12-lead electrocardiogram (ECG), vital signs and Adverse Event/ Serious Adverse
      Event (AE/ SAE) recording.
    

Detailed description: 
      GSK2190915 is a high affinity 5-lipoxygenase-activating protein (FLAP) inhibitor that
      attenuates the production of leukotrienes, through the blockage of the first committed step
      in the leukotriene pathway, 5 lipoxygenase (5-LO) activation. Leukotrienes are potent
      inflammatory molecules produced mainly by mast cells, eosinophils, monocytes/macrophage and
      neutrophils in response to allergic or inflammatory stimuli.

      Clinical studies conducted to date with GSK2190915 have utilised an aqueous formulation of
      the compound. However, to progress the compound further in clinical development, a solid dose
      formulation is necessary. This study will evaluate the optimal capsule formulation from a
      selection of three available capsule formulations, and a dose, that can be taken forward for
      future clinical development. Since it is expected that the compound will be developed for
      Chronic Obstructive Pulmonary Disease (COPD), the study will also include a repeat-dose
      cohort with elderly subjects (smokers and non-smokers over 65 years of age) in order to
      evaluate the repeat-dose derived pharmacokinetic parameters of the selected capsule
      formulation in this population.

      This is a multi-cohort study and upto 6 cohorts will be performed.

      In cohort 1, the bioavailability of single doses of 50 milligrammes (50 mg) of three capsule
      formulations (capsule formulations A, B and C) in the fasted state will be assessed.
      Depending on the bioavailability data obtained from cohort 1, one, two or three capsule
      formulations may be taken forward into cohort 2.

      If only one formulation is deemed to be suitable for progression, cohort 2 will be a
      single-dose, 4-way complete crossover study to investigate both food-effect and dose
      proportionality in 10 healthy adult subjects. The decision to progress this formulation to
      the final (repeat-dose) cohort (cohort 4) will be made based on favourable food interaction
      and proportionality in bioavailability between high and low doses in cohort 2.

      If more than one capsule formulation fulfils the bioavailability criteria following cohort 1,
      cohort 2 will be a food-effect study with a 100mg single dose of two or three selected
      capsule formulations in healthy adult subjects. Progression to Cohort 3 will be dependent on
      the formulation/s meeting predetermined pharmacokinetic (PK) criteria. Cohort 3 will be a
      complete crossover study with single doses of 20mg and 200mg of each of upto two capsule
      formulations taken forward from cohort 2 in 10 healthy adult subjects in the fasted state.
      The aim of performing this cohort is to explore the dose proportionality between low and high
      doses of the two selected capsule formulations.

      Cohort 4 is a 12-day repeat-dose, double-blinded, placebo-controlled study in 12 healthy
      elderly subjects (>65 years) in the fed or fasted state with once-daily dosing of the highest
      dose (200mg) of the capsule formulation (A, B or C) taken forward from the previous cohorts.
      The aim of this cohort is to investigate the accumulation of the selected formulation during
      repeat dosing.

      Cohort 5 will be a 4-way complete crossover study with single doses of 100mg of two tablet
      formulations (milled and micronised) administered to healthy volunteers in the fed and fasted
      states. The aim of performing this cohort is to explore the single-dose pharmacokinetics of
      the two tablet formulations with a view to assessing their suitability for use in subsequent
      late- phase studies.

      Cohort 6 will be a 4-way complete crossover study with single doses of 100mg of two modified
      tablet formulations (different from Cohort 5 formulations) administered to healthy volunteers
      in the fed and fasted states. The aim of performing this cohort is to explore the single-dose
      pharmacokinetics of the two modified tablet formulations with a view to assessing their
      suitability for use in subsequent late- phase studies.
    

Intervention name(s): GSK2190915 Solution.; GSK2190915 Granule Capsule (A); GSK2190915 Semi-solid Lipid Capsule (B); GSK2190915 Liquid Lipid Capsule (C); GSK2190915 Milled Tablet; GSK2190915 Micronised Tablet
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Aqueous Solution, 10mg/mL.; GSK2190915A granule filled in to Gelatin capsules; GSK2190915A dispersed in a lipid vehicle and filled in to HPMC capsules; GSK2190915A dissolved in lipid vehicle milled and filled in to Gelatin capsules; GSK2190915A granule is blended, compressed into tablets and aqueous film coated; GSK2190915A granule is blended, compressed into tablets and aqueous film coated
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: FLAP inhibitor; Chronic Obstructive Pulmonary Disease (COPD); COPD; Bioavailability