A Repeat Dose Study to Investigate the Interaction of GSK2190915 on the Pharmacokinetics of Rosuvastatin
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 1

Summary: 
      Leukotrienes are potent inflammatory molecules produced mainly by mast cells, eosinophils,
      monocytes/macrophage and neutrophils in response to allergic or inflammatory stimuli.
      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.

      GSK2190915 has been shown to be an in vitro inhibitor of human organic anion transporting
      polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), hence there is a potential for a
      pharmacokinetic drug-drug interaction with OATP1/ B1 substrates such as the anti-lipidemic
      rosuvastatin.

      This study will evaluate the effect of repeat oral dosing of GSK2190915 (30milligram (mg) and
      100mg) on the steady-state pharmacokinetics (PK) of rosuvastatin (10 mg). In addition, the
      study will evaluate the safety and tolerability of this combination when co-administered to
      healthy, adult volunteers in two cohorts.
    

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. As GSK2190915 inhibits the
      production of leukotriene B4 and cysteinyl leukotrienes it has strong potential utility in
      the treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD) The organic anion
      transporting polypeptides (OATP's) form a superfamily of sodium-independent transport systems
      that mediate the transmembrane transport of a wide range of amphipathic organic compounds. Of
      the 11 human OATP transporters, OATP1B1, and OATP1B3 are specifically expressed on the
      sinusoidal membrane of hepatocytes and are considered to be of particular importance for
      hepatic drug elimination and drug pharmacokinetics.

      GSK2190915 has been shown to be an inhibitor of OATP1B1 and OATP1B3. Several clinically
      utilised drugs have been identified as substrates of OATP transporters, including
      rosuvastatin - a member of the statin group of anti-lipidemics.

      As the target patient population for GSK2190915 may overlap with that for statins such as
      rosuvastatin, it is important to evaluate any potential effects of GSK2190915 on the
      pharmacokinetics of a statin known to undergo hepatic elimination via OATP1B1/1B3 This study
      will evaluate the effect of repeat oral dosing of GSK2190915 on the steady-state
      pharmacokinetics of rosuvastatin. In addition, the study will evaluate the safety and
      tolerability of this combination when co-administered to healthy, adult volunteers.

      Two dose levels of GSK2190915 will be investigated; 30mg and 100mg once daily for 7 days. The
      rosuvastatin dose selected for this study is 10mg which allows for up to a 4 times increase
      in systemic exposure if there is a pharmacokinetic interaction.

      The study will be an open label, single-sequence study in two cohorts with 2 treatment
      periods. 28 subjects will receive rosuvastatin 10mg/day for 7 days during the first treatment
      period, following on from which 14 subjects each will receive either GSK2190915 30 mg/day or
      GSK2190915 100mg/day in combination with rosuvastatin 10mg/day for the next 7 days. Subjects
      will be followed up 7-14 days after their last dose. PK samples will be obtained for both
      rosuvastatin and GSK2190915 during the study. Safety will be evaluated via physical
      examinations, ElectroCardioGrams (ECG) and vital signs.

      Approximately 28 healthy subjects will be enrolled such that approximately 24 subjects (12 in
      each of the two treatment arms) complete dosing and critical assessments.
    

Intervention name(s): Rosuvastatin 10 mg; GSK2190915 30mg; GSK2190915 100mg
Intervention type(s): Drug; Drug; Drug
Intervention description(s): days 1-14; 1x30mg tablet, days 8-14; 1x100mg tablet, days 8-14
Intervention MeSH terms: Rosuvastatin Calcium
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Drug-drug interaction; rosuvastatin; asthma; FLAP inhibitor