AstraZeneca R&D Alderley Park Macclesfield, Cheshire, SK10 4TG, United Kingdom.
Pharmacol Res Perspect. 2015 Oct;3(5):e00176. doi: 10.1002/prp2.176. Epub 2015 Sep 15.
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.
福他替尼是一种针对脾酪氨酸激酶的酪氨酸激酶抑制剂，已完成类风湿关节炎患者的临床试验。在临床研究中，福他替尼治疗与全身动脉血压（BP）的轻微升高相关，这与其他激酶抑制剂的发现相似，尤其是那些抑制 VEGFR2 信号的抑制剂。我们已经研究了福他替尼引起的血压升高与在清醒大鼠中的福他替尼活性代谢物 R940406 的血浆水平之间的联系，并且发现血压效应的时间过程与 R940406 血浆浓度的变化密切相关，表明存在直接的药理关系。在这些研究中产生的游离血浆 R940406 水平（高达 346 nmol/L）跨越了临床上观察到的平均游离血浆峰浓度 49 nmol/L。我们已经证明，通过多种方法可以成功控制福他替尼给药引起的血压升高，特别是简单地停药或与一系列标准抗高血压药物如阿替洛尔、卡托普利和硝苯地平联合用药。这些发现支持在福他替尼治疗期间保持患者安全的潜在方法。此外，我们使用硝苯地平作为示例药物证明，通过降低 R940406 的血浆暴露，不能实现这种血压控制，这表明在通过使用标准联合用药来管理血压控制的同时，可以维持研究药物的药理学的潜在益处。
