2022 年第 5 期 第 17 卷

胺碘酮和去乙基胺碘酮健康人体复合生理药动学模型建立及组织分布特征预测

Establishment of a complex physiologically based pharmacokinetic modeling of amiodarone and desethylamiodarone in healthy subjects and their tissue distribution prediction

作者：杜海燕1刘文芳1谭莉1仇琪1周子杰1王钰玺2林阳1

英文作者：Du Haiyan1 Liu Wenfang1 Tan Li1 Qiu Qi1 Zhou Zijie1 Wang Yuxi2 Lin Yang1

单位：1首都医科大学附属北京安贞医院药事部，北京100029；2上海凡默谷信息技术有限公司，上海200120

英文单位：1Department of Pharmacy Beijing Anzhen Hospital Capital Medical University Beijing 100029 China; 2PharmoGo Co. Ltd. Shanghai 200120 China

关键词：生理药动学模型；胺碘酮；去乙基胺碘酮；组织分布

英文关键词：Physiologicallybasedpharmacokineticmodeling;Amiodarone;Desethylamiodarone;Tissuedistribution

• 摘要：

• 目的 建立并验证胺碘酮及其活性代谢产物去乙基胺碘酮(DEA)的复合生理药动学(PBPK)模型，进而预测胺碘酮和DEA在健康人体各组织器官中的分布特征。方法 检索中国知网、ScienceDirect和PubMed等数据库中关于胺碘酮和DEA的理化常数和药动学性质的相关文献，运用GastroPlusTM Version 9.8软件建立、优化并验证胺碘酮静脉滴注或口服给药的健康人体PBPK模型，通过药动学参数预测值和实测值倍数误差评价模型有效性。采用PBPK模型结合药物特异性参数，应用血流灌注限速模式预测胺碘酮及DEA在各组织器官中的分布特征。结果利用已发表的日本人群静脉滴注给药5 mg/kg剂量组数据进行PBPK建模，然后利用2.5 mg/kg剂量组的实测数据进行模型验证。模型预测的药动学参数值与实测值的比值基本均在0.5～2.0，说明模型可靠。用中国人群单次口服实测数据进行模型验证，模型预测的药动学参数值与实测值的比值均在0.5～2.0，验证模型适合于中国人群。胺碘酮、DEA在肝、肺、心、肾、脂肪等组织中浓度均远高于血浆浓度，其中在脂肪中浓度升高具有明显的滞后效应，消除半衰期很长。结论  通过建立并验证胺碘酮及DEA复合PBPK模型预测发现，胺碘酮、DEA在肝、肺、心、肾、脂肪中的浓度均远高于血浆浓度，且在脂肪组织中浓度升高滞后于其他组织，为进一步评估胺碘酮的临床有效性和安全性提供了药动学依据。

• Objective  To establish and verify a complex physiologically based pharmacokinetic (PBPK) modeling of amiodarone(AMIO) and its active metabolite, desethylamiodarone(DEA), and to predict tissue distribution characteristics of them for tissues and organs in healthy objects. Methods The literature from China National Knowledge Infrastructure, ScienceDirect, PubMed and other databases was searched for relevant information on physicochemical constants and pharmacokinetic properties of AMIO and DEA. The healthy human PBPK modeling of intravenous or oral administration of AMIO was established, optimized and verified by GastroPlusTM Version 9.8 software. The effectiveness of the model was evaluated by the multiple errors of the predicted and measured values of pharmacokinetic parameters. The PBPK modeling combined with drug specific parameters was used to predict the distribution characteristics of AMIO and DEA in various tissues and organs based on perfusion rate limiting mode. Results  The published data of intravenous drip dose group of 5 mg/kg in Japanese population were used for PBPK modeling, and then the measured data of 2.5 mg/kg dose group were used for model verification. The ratio of the predicted pharmacokinetic parameters to the measured values was basically 0.5-2.0, indicating that the modeling was reliable. The modeling was verified with the measured data of single oral administration in Chinese population. It was found that the ratio of the predicted pharmacokinetic parameters to the measured values was 0.5-2.0. The validation model was suitable for Chinese population. The concentrations of AMIO and DEA in liver, lung, heart, kidney, fat and other tissues were much higher than those in plasma, in which increase of concentration there was an obvious lag effect in fat and the elimination half-life was long. Conclusions Through the established and validated PBPK modeling of AMIO and DEA, it is found that the concentrations of AMIO and DEA in liver, lung, heart, kidney and fat are much higher than those in plasma, and the increase of concentration in fat lags behind that in other tissues. It provides a pharmacokinetic basis for further evaluating the clinical efficacy and safety of AMIO.