A Repeat Dose Study to Investigate the Interaction of GSK2190915 on the Pharmacokinetics of Rosuvastatin
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.
Drug: Rosuvastatin 10 mg
Drug: GSK2190915 30mg
Drug: GSK2190915 100mg
|Study Design:||Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||An Open Label, Sequential, Single Cohort, Repeat Dose Study to Investigate the Potential Interaction of GSK2190915 on the Pharmacokinetics of Rosuvastatin in Healthy Adult Subjects.|
- Maximum Concentration (Cmax) of rosuvastatin [ Time Frame: On 7 and 14 days post- first dose ] [ Designated as safety issue: No ]
- Area Under the Curve(0-τ) of rosuvastatin [ Time Frame: On 7 and 14 days post first dose ] [ Designated as safety issue: No ]
- Safety and tolerability as assessed by clinical monitoring of blood pressure, pulse rate, ECG monitoring and laboratory safety data, as well as reporting of Adverse Events in healthy adult subjects from dosing to one week post-dose. [ Time Frame: From screening to follow-up visit ] [ Designated as safety issue: Yes ]
|Study Start Date:||January 2011|
|Study Completion Date:||February 2011|
|Primary Completion Date:||February 2011 (Final data collection date for primary outcome measure)|
|Active Comparator: Rosuvastatin foll by GSK2190915 30mg + rosuvastatin||
Drug: Rosuvastatin 10 mg
days 1-14Drug: GSK2190915 30mg
1x30mg tablet, days 8-14
|Active Comparator: Rosuvastatin foll by GSK2190915 100mg + rosuvastatin||
Drug: Rosuvastatin 10 mg
days 1-14Drug: GSK2190915 100mg
1x100mg tablet, days 8-14
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01411111
|GSK Investigational Site|
|London, United Kingdom, NW10 7EW|
|Study Director:||GSK Clinical Trials||GlaxoSmithKline|