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应用生理药动学模型预测酮康唑和地拉韦啶对替格瑞洛药动学特征和药效学的影响 被引量:1

Application of physiologically based on pharmacokinetic model in predicting the effect of ketoconazole and delavirdine on the pharmacokinetic and pharmacodynamic characteristics of ticagrelor
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摘要 目的:建立替格瑞洛(ticagrelor)与竞争性抑制剂酮康唑(ketoconazole)及时间依赖性抑制剂地拉韦啶(delavirdine)联合应用的药物相互作用(DDIs)的动态模型和PKPD模型.采用该DDIs模型和PKPD模型预测两种不同类型的抑制剂对替格瑞洛药动学特征和药效学的影响,为指导临床合理用药提供理论依据.方法:通过文献检索以及ADMETPredictor预测,收集获取替格瑞洛、酮康唑和地拉韦啶的理化性质参数、生物药剂学参数、药物代谢酶促反应参数、人体生理参数等;同时收集替格瑞洛与代谢物AR-C124910XX的血药浓度(PK)及药效学(PD)数据,建立并验证三者的生理药动学(physiologically based pharmacokinetic,PBPK)模型与血药浓度(PK)-药效学(PD)结合模型.结合酮康唑与地拉韦啶的酶抑制参数与酶降解速率常数,分别建立其与替格瑞洛的DDIs动态模型,预测2种抑制剂引起替格瑞洛及其活性代谢物的药动学变化的过程;再根据PKPD结合模型,预测两种抑制剂对替格瑞洛的药效影响.结果:替格瑞洛与酮康唑的DDIs动态模型显示,合用后替格瑞洛在体内的Cmax,AUC0-inf和AUC0-t值均增加,分别增加至单独服用的2.07倍、3.70倍及3.76倍;替格瑞洛与地拉韦啶的DDIs动态模型显示,合用后替格瑞洛在体内的Cmax,AUC0-inf和AUC0-t值均增加,分别增加至单独服用的1.66倍,2.66倍和2.68倍.替格瑞洛的PKPD结合模型显示,酮康唑会使替格瑞洛在体内的I48h(%),AUEC0-t及AUEC0-inf和t1/2值均有大幅度增加,分别增加至单独服用的1.80倍、1.27倍、1.67倍和3.11倍;地拉韦啶会使替格瑞洛在体内的I48h(%),AUEC0-t及AUEC0-inf和t1/2值均有较大程度增加,分别增加至单独服用的1.83倍、1.27倍、1.91倍和3.23倍.结论:从药物相互作用结果分析,抑制剂酮康唑、地拉韦啶会使替格瑞洛的血药浓度大幅度增加.对于替格瑞洛而言,2种抑制剂分别与其联合使用时,替格瑞洛的剂量均需要调整.� OBJECTIVE To establish dynamic drug-drug interactions models and PKPD models between ticagrelor with keto-conazole which was the competitive inhibitor and ticagrelor with delavirdine which was the time dependent inhibitor.The DDIs models and PKPD models could provide a theoretical reference for clinical rational administration by means of predicting the effects of two different inhibitors on the pharmacokinetics and pharmacodynamics of ticagrelor.METHODS Physicochemical properties,biopharmaceutical parameters,parameters of enzymatic reaction were collected for drug metabolism,physiological parameters of human body,etc.for ticagrelor,ketoconazole and delavirdine by document index and ADMET Predictor.Mean-while,blood concentration(PK)data and pharmacodynamics(PD)data were collected for ticagrelor and AR-C124910XX,which were the metabolites of ticagrelor.The combined model of physiological pharmacokinetics and blood concentration(PK )-phar-macodynamics(PD)were established and validated for the three drugs.Then DDIs dynamic models of ketoconazole and delavirdine were respectively established combining with enzyme inhibition parameters and enzymatic degradation rate constant to predict changes in the pharmacokinetic process of ticagrelor and AR-C124910XX.Furthermore,the effects of two inhibitors on the pharmacodynamic changes of ticagrelor were predicted,according to the PKPD binding model.RESULTS The DDIs dynamic model of ticagrelor and ketoconazole showed that,C max,AUC 0-inf and AUC 0-t of ticagrelor were increased by 2.07times,3.70 times and 3.76times,respectively.And the DDIs dynamic model of ketoconazole and delavirdine showed that,C max,AUC 0-inf and AUC 0-t of ticagrelor were increased by 1.66times,2.66times and 2.68times,respectively.The PKPD binding model of ticagrelor showed that,I 48h(% ), AUEC 0-t,AUEC 0-inf and t 1/2 values increased to 1.80times,1.27times,1.67times and 3.11 times,respectively by ketoconazole,and increased to 1.83times,1.27times,1.91 times and 3.23 times,respectively by dela-virdine.CONC
作者 任佳伟 韩星 李彦萍 刘洋 汪国鹏 REN Jia-wei;HAN Xing;LI Yan-ping;LIU Yang;WANG Guo-peng(North China Electric Power University,Beijing 102206, China;Beijing University of Chinese Medicine,School of Chinese Materia Medica,Beijing 100102, China;Zhongcai Health (Beijing) Biological Technology Development Co., Ltd., Beijing 101503, China)
出处 《中国医院药学杂志》 北大核心 2018年第24期2552-2558,2575共8页 Chinese Journal of Hospital Pharmacy
关键词 替格瑞洛 酮康唑 地拉韦啶 生理药动学模型 药物相互作用模型 时间依赖性抑制 药动药效结合模型 ticagrelor ketoconazole delavirdine physiologically based pharmacokinetic model drug -druginteraction mod -el time dependant inhibition PKPD
作者简介 任佳伟,男,主管药师,硕士,研究方向:药学和中药学,电话:010-61773286,E-mail:rjwticagrelor@sina.cn;通讯作者:汪国鹏,男,硕士,E-mail:binglelly@163.com
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