Fostamatinib is a
tyrosine kinase inhibitor with activity against
spleen tyrosine kinase which has completed clinical trials for patients with
rheumatoid arthritis. In clinical studies
fostamatinib treatment was associated with a small elevation of systemic arterial blood pressure (BP), a similar finding to that seen with other
kinase inhibitors, especially those that inhibit VEGFR2 signaling. We have investigated the link between
fostamatinib-induced blood pressure elevation and plasma levels of the
fostamatinib-active metabolite R940406 in conscious rats and found the time course of the BP effect correlated closely with changes in R940406 plasma concentration, indicating a direct pharmacological relationship. Free plasma levels of R940406 produced in these studies (up to 346 nmol/L) span the clinically observed mean peak free plasma concentration of 49 nmol/L. We have demonstrated that the blood pressure elevation induced by
fostamatinib dosing can be successfully controlled by a variety of methods, notably simple drug withdrawal or codosing with a range of standard
antihypertensive agents such as
atenolol,
captopril, and
nifedipine. These findings support potential methods of maintaining patient safety while on
fostamatinib therapy. Furthermore, we have demonstrated, using
nifedipine as an example agent, that this blood pressure control was not achieved by reduction in plasma exposure of R940406, suggesting that potential benefits from the pharmacology of the
investigational drug can be maintained while blood pressure control is managed by use of standard comedications.