Background/Purpose: Fostamatinib is a kinase inhibitor with activity at spleen tyrosine kinase. In clinical studies in patients with rheumatoid arthritis, fostamatinib treatment was associated with an increase in arterial blood pressure (BP). Some tyrosine kinase inhibitors are known to cause BP elevation, potentially by inhibiting vascular endothelial growth factor receptor 2 (VEGFR2). Therefore, we investigated whether there was a mechanistic link between fostamatinib-induced BP elevation and inhibition of VEGF signaling.

Methods: BP was measured in conscious rats using combined automated blood sampling and radio telemetry following oral dosing with fostamatinib. The effects of intravenous dosing of R406 (the active metabolite of fostamatinib) on BP, femoral vascular conductance and responses to acetylcholine (ACh), reactive hyperemia and VEGF were assessed in rats anesthetized with isofluorane (0.5 to 5%). The effects of R406 on contractile parameters were determined using rat isolated aorta and human resistance vessels in vitro. The effects of R406 on VEGF-stimulated nitric oxide production were determined using human microvascular endothelial cells in vitro. VEGFR2 phosphorylation was determined in mouse lung, ex vivo, following oral dosing with fostamatinib.

Results: In conscious rats, fostamatinib caused a dose-dependent increase in BP. The time course of the BP effect correlated closely with changes in R406 plasma concentration, consistent with a direct pharmacologic relationship. In anesthetized rats, infusion of R406 increased BP and decreased femoral arterial conductance. Endothelial function was not reduced, as infusion of R406 did not inhibit hyperemia- or ACh-induced vasodilatation in rats. R406 had no effect on the contraction of intact isolated vessels, suggesting the decreased arterial conductance was an indirect effect. R406 inhibited VEGF-stimulated nitric oxide production from human endothelial cells in vitro, and treatment with R406 inhibited VEGFR2 phosphorylation in vivo. R406 also inhibited VEGF-induced hypotension in anesthetized rats (see Figure).

Conclusion: These data suggest that increased vascular resistance, potentially secondary to reduced VEGF-induced nitric oxide release from the endothelium, may contribute to BP increases observed with fostamatinib. This is consistent with the means by which other drugs that inhibit VEGF signaling elevate BP, although the contribution of other mechanisms cannot be excluded.

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