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GSK2646264, a spleen tyrosine kinase inhibitor attenuates the release of histamine in ex vivo human skin.

BACKGROUND AND PURPOSE: Chronic Spontaneous Urticaria presents as a heterogeneous syndrome characterised by wheals, angioedema or both for greater than six weeks. Spleen tyrosine kinase (SYK) mediates allergen-induced mast cell degranulation via the IgE signalling pathway, a central component of wheal formation and inflammation. In this study, we demonstrate that perfused or topically administered GSK2646264 dose dependently attenuates IgE-mediated histamine release from mast cells in an ex vivo human skin model.

EXPERIMENTAL APPROACH: Using a novel SKIP device ex vivo human skin from mastectomy surgeries was challenged with anti-IgE, C5a and buffer to induce histamine release from skin mast cells. Histamine was collected via microdialysis fibers and measured fluorometrically. GSK2646264, was delivered via perfusion either using the microdialysis fibers or topically in a cream. Drug concentrations in the skin were measured by LC-MS and a PK/PD relationship was developed.

KEY RESULTS: Perfused GSK2646264 significantly inhibited anti-IgE (but not C5a) induced histamine release in a concentration dependent manner (IC50 =0.7 μM, IC90 = 6.8 μM). The 0.5, 1 and 3% cream delivered GSK2646264 to the dermis above the IC90 (donor range 9.4 - 550 μM) and dose dependently attenuated the anti-IgE induced histamine release.

CONCLUSIONS AND IMPLICATIONS: GSK2646264 administered topically or direct to the dermis blocked histamine release from in situ skin mast cells. A PK/PD relationship curve suggests that dermal concentrations above 6.8 μM should lead to approximately 90% inhibition of histamine release from skin mast cells following FcεRI activation implicating a potential use for the compound in skin mast cell diseases such as urticaria.

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