A Study to Look at How GSK1325756 is Taken up by the Body When Given by Mouth When Stomach Acid is Reduced
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Pulmonary Disease, Chronic Obstructive
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a Phase I study to assess the combined effects of food and suppression of gastric
      acid secretion on the relative bioavailability of an immediate release (IR) tablet
      formulation and prototype bioenhanced formulations of GSK1325756, an oral interleukin 8
      receptor (IL8R also known as CXCR2) antagonist. The objectives are to understand if the
      co-administration of food enhances absorption and the inter-subject variability for the
      current GSK1325756 IR tablet under fed state proton pump inhibitor (PPI) conditions and
      secondly to assess whether two proposed bioenhanced formulations offer any improvement over
      the current GSK1325756 IR formulation under PPI conditions.

      This open-label, randomized, 5-period crossover study will be completed in a single cohort of
      subjects, with an interim analysis after completion of Treatment Period 4. During Treatment
      Periods 1 to 4, subjects will be randomized to receive GSK1325756 50 mg IR in the fed state,
      GSK1325756 50 mg IR in the fasted state, GSK1325756 Bioenhanced Formulation 1 in the fasted
      state, and GSK1325756 Bioenhanced Formulation 2 in the fasted state. Progression to Treatment
      Period 5 and the choice of bioenhanced formulation for dosing in this treatment period will
      be dependent on the findings of an interim analysis of the pharmacokinetic profile and
      relative bioavailability of each formulation following completion of Treatment Periods 1 to
      4. In Treatment Period 5, subjects will receive the selected GSK1325756 bioenhanced
      formulation in the fed state.
    

Detailed description: 
      The primary objective of this study is to evaluate the relative bioavailability, including
      the inter-subject variability, of the immediate release (IR) tablet used for the previous
      Phase I studies and 2 prototype bioenhanced tablet formulations of GSK1325756 in healthy
      elderly male and female subjects under fed and fasted states during suppression of gastric
      acid secretion (concomitant omeprazole, 20 mg, once daily (QD)). Secondary objectives include
      provision of information on the oral pharmacokinetic (PK) of GSK1325756 in the elderly under
      different dosing conditions during suppression of gastric acid secretion, and additional
      safety and tolerability information for oral administration of GSK1325756 in elderly
      subjects.

      The current study will provide an understanding of the PK of three formulations of GSK1325756
      during gastric acid suppression in a population of 65 to 80 year old healthy adult subjects.
      The effect of food on the PK of each GSK1325756 formulation will also be addressed in this
      population. The outcome of this study is likely to guide selection of the most appropriate
      formulation/dosing regimen for future studies.

      The completed clinical studies demonstrated that to minimize inter-subject variability of the
      exposure to GSK1325756, the current formulation needs to be administered with food,
      particularly in elderly subjects. This does not preclude development of the current
      formulation, but is not ideal, particularly if twice daily administration is needed in
      chronic obstructive pulmonary disease (COPD) patients and for elderly subjects in which food
      intake can be variable. In addition, the inter-subject variability in exposure with the
      current formulation when given with omeprazole in the fasted state is not acceptable. This is
      likely due to the need for a low pH (acid level) (pH < 2) gastric environment, particularly
      in the fasted state, to allow for sufficient solubilization of the GSK1325756 prior to
      transport to the small intestine where it is absorbed. Thus, this study is being conducted
      for the following reasons: (1) to determine if the current formulation results in acceptable
      exposure and inter-subject variability if given with food in subjects in which gastric acid
      secretion is suppressed with omeprazole and (2) to determine if a bio-enhanced formulation
      can provide an acceptable exposure profile and acceptable inter-subject variability in the
      fasted state in subjects in which gastric acid is suppressed. This information will be
      important in helping to determine the appropriate formulation and dosing regimen for
      progression to studies in COPD patients.
    

Intervention name(s): GSK1325756
Intervention type(s): Drug
Intervention description(s): CXCR2 antagonist
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Other