Sunitinib is an oral small molecule multitargeted tyrosine kinase inhibitor, which is currently used to treat severe cancers. Clinical research has shown that patients treated with sunitinib develop hypertension. As soon as sunitinib-induced hypertension appears, it is usual to administer anti-hypertension agent. But this treatment may cause acute blood pressure fluctuation which may lead to additional cardiovascular risk. The aim of this study is to establish a mathematical model for managing sunitinib-induced hypertension and blood pressure fluctuation. A mechanism-based PK/PD model was developed based on animal experiments. Then this model was used to perform simulations, thus to propose an anti-hypertension indication, according to which the anti-hypertension treatment might yield relative low-level AUC and fluctuation of blood pressure. The simulation results suggest that the anti-hypertension agent may yield low-level AUC and fluctuation of blood pressure when relative ET-1 level ranges from −15% to 5% and relative NO level is more than 10% compared to control group. Finally, animal experiments were conducted to verify the simulation results. Macitentan (30 mg/kg) was administered based on the above anti-hypertension indication. Compared with the untreated group, the optimized treatment significantly reduced the AUC of blood pressure; meanwhile the fluctuation of blood pressure in optimized treatment group was 70% less than that in immediate treatment group. This work provides a novel model with potential translational value for managing sunitinib-induced hypertension.

舒尼替尼是一种口服小分子多靶点酪氨酸激酶抑制剂，目前用于治疗严重癌症。临床研究表明，接受舒尼替尼治疗的患者会出现高血压。一旦出现舒尼替尼诱发的高血压，通常给予抗高血压药物。但这种治疗可能会导致急性血压波动，从而导致额外的心血管风险。本研究的目的是建立一个管理舒尼替尼引起的高血压和血压波动的数学模型。基于动物实验开发了基于机制的 PK/PD 模型。然后将该模型用于进行模拟，从而提出抗高血压适应症，根据该适应症，抗高血压治疗可能会产生相对较低的AUC和血压波动。模拟结果表明，与对照组相比，当相对 ET-1 水平在 -15% 至 5% 和相对 NO 水平超过 10% 时，抗高血压药物可能会产生低水平的 AUC 和血压波动。最后通过动物实验验证了模拟结果。根据上述抗高血压适应症给予马西替坦（30 mg/kg）。与未治疗组相比，优化治疗组血压AUC显着降低；同时优化治疗组血压波动较即刻治疗组减少70%。这项工作为管理舒尼替尼诱发的高血压提供了一种具有潜在转化价值的新模型。