Prevention of fostamatinib-induced blood pressure elevation by antihypertensive agents

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.