PK/PD modeling based on NO-ET homeostasis for improving management of sunitinib-induced hypertension in rats  

作　　者：Hao-chen Liu Xiao-ting Zhou Yun-si Zheng Hua He Xiao-quan Liu 

机构地区：[1]Center of Drug Metabolism and Pharmacokinetics,China Pharmaceutical University,Nanjing 210009,China

出　　处：《Acta Pharmacologica Sinica》2020年第5期719-728,共10页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(no.81773806 and no.81503145);“Double First-Class”University Project(no.CPU2018GY19);the Fundamental Research Funds for the Central Universities(no.2632018ZD10).

摘　　要：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 pressurefluctuation 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 pressurefluctuation.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 andfluctuation of blood pressure.The simulation results suggest that the anti-hypertension agent may yield low-level AUC andfluctuation 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 thefluctuation 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.

关 键 词：SUNITINIB HYPERTENSION blood pressurefluctuation PK/PD modeling simulation macitentan 

分 类 号：R965[医药卫生—药理学]