基于PBPK建模预测替格瑞洛在人体内的药动学行为

Prediction of pharmacokinetics behaviors of oral ticagrelor in human based on physiologically based pharmacokinetic model

目的:建立替格瑞洛在健康人群中的生理药动学(PBPK)模型,预测其口服给药后在人体的吸收部位与吸收量及组织分布特征,为预测替格瑞洛药物互相作用和临床治疗提供参考依据。方法:通过文献和ADMET Predictor软件计算获取替格瑞洛建模的理化参数及生物药剂学参数,通过替格瑞洛注射给药的药动学数据获取替格瑞洛在人体的清除率(CL),应用Gastro PlusTM软件建立替格瑞洛口服给药的PBPK预测模型,并对模型进行验证和优化。通过所建立的预测模型,能预测药物体内药-时曲线,预测药物吸收部位与吸收量及口服给药后药物在各个组织及器官中的药物暴露量。结果:模型拟合替格瑞洛的药-时曲线与实测值的平均折合误差(AFE)和绝对平均折合误差(AAFE)值分别为1.0和1.1,这表明所建立的PBPK模型有效性良好。药物主要的吸收部位为空肠,吸收量为35.8%。口服替格瑞洛后,药物在身体各个组织中均有广泛的分布,其在脂肪组织、红骨髓和黄骨髓中的药物显露量约是血中药物暴露量1.6倍。结论:所建立的PBPK模型可较好模拟替格瑞洛口服给药后的体内药动学行为,对于预测药物可能的相互作用及临床给药方案有指导意义。

OBJECTIVE To develop a physiologically based pharmacokinetic（ PBPK） model of ticagrelor for predicting regional absorption fraction and tissue distribution features in human after oral administration,provide a basis for drug-drug interactions and clinical treatment of ticagrelor. METHODS By obtaining drug specific properties such as Log P,protein binding,blood/plasma ratio,solubility,effective permeability and clearance from published literatures and computing results from ADMET Predictor,PBPK model of ticagrelor was built and optimized by Gastro PlusTMsoftware. Pharmacokinetic parameters,such as blood concentrations profile,regional absorption fraction and body distribution of different tissue compartments of ticagrelor in healthy male volunteers were forecasted after oral administration. RESULTS An AFE of 1. 0（ AFE 〈2） and an AAFE of 1. 1（ AAFE〈3） showed the good prediction between observed and simulated concentration-time profile. The regional absorption fraction predicted suggested that the majority of ticagrelor was absorbed in jejunum by 35. 8 %,and it was widely distributed in human body after administration. Exposures of Ticagrelor in yellow marrow,adipose and red marrow were about 1. 6 times of the blood drug exposure. CONCLUSION The proposed PBPK model can accurately simulate the pharmacokinetic behavior of ticagrelor in human,which is of good guidance to the prediction of drugdrug interactions and clinical dosage regimen of ticagrelor.