Physiology-Based Simulations of a Pathological Condition Prediction of Pharmacokinetics in Patients with Liver Cirrhosis
Physiology-Based Simulations of a Pathological Condition Prediction of Pharmacokinetics in Patients with Liver Cirrhosis
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DOI：
10.2165/00003088-200847110-00005
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发表时间：
2008-01-01
影响因子：
4.5
通讯作者：
Willmann, Stefan
中科院分区：
文献类型：
--
作者：
Edginton, Andrea N.;Willmann, Stefan
工作背景：肝硬化是一种进行性疾病，其特征在于肝细胞功能丧失，伴随着肝脏中结缔组织和结节形成。与疾病相关的形态学和生理学变化实质上影响药物药代动力学。全身生理药代动力学（Whole-body physiological based pharmacokinetics，WB-PBPK）模型是一种将药物的药代动力学参数与肝硬化患者的生理状态定量联系起来的预测技术，目的：基于肝硬化患者的生理变化，对已有的WB-PBPK模型进行扩展，使其能够预测肝硬化患者的药物药代动力学。对文献进行了检索，以定量测量与Child-Pugh A级至C级肝硬化相关的生理变化。包括的参数是器官血流量、心脏指数、血浆结合蛋白浓度、红细胞压积、功能性肝体积、肝酶活性和肾小球滤过率。将模型化合物阿芬太尼、利多卡因（利多卡因）、茶碱和左乙拉西坦的药代动力学曲线和参数的预测值与文献数据进行比较。结果：阿芬太尼和利多卡因的预测血药浓度-时间曲线与实测血药浓度-时间曲线相似，因此与Child-Pugh A、B和C级肝硬化相关的药代动力学变化得到了充分描述。与对照组相比，Child-Pugh分级B和C级患者的茶碱消除半衰期显著延长，与模型预测一致。左乙拉西坦的尿排泄一贯减少与疾病的进展和非常密切相似的观察values.Conclusion：考虑健康人和肝硬化患者之间的生理差异是重要的模拟药物药代动力学在这一妥协组。改变WB-PBPK模型，以将这些生理差异与药物药代动力学的充分模拟结果相结合。本研究提供的信息将允许其他研究人员在WB-PBPK模型中进一步验证该肝硬化模型。
Background: Liver cirrhosis is a progressive disease characterized by loss of functional hepatocytes with concomitant connective tissue and nodule formation in the liver. The morphological and physiological changes associated with the disease substantially affect drug pharmacokinetics. Whole-body physiologically based pharmacokinetic (WB-PBPK) modelling is a predictive technique that quantitatively relates the pharmacokinetic parameters of a drug to such (patho-)physiological conditions.Objective: To extend an existing WB-PBPK model, based on the physiological changes associated with liver cirrhosis, which allows for prediction of drug pharmacokinetics in patients with liver cirrhosis.Methods: The literature was searched for quantitative measures of the physiological changes associated with the presence of Child-Pugh class A through C liver cirrhosis. The parameters that were included were the organ blood flows, cardiac index, plasma binding protein concentrations, haematocrit, functional liver volume, hepatic enzymatic activity and glomerular filtration rate. Predictions of pharmacokinetic profiles and parameters were compared with literature data for the model compounds alfentanil, lidocaine (lignocaine), theophylline and levetiracetam.Results: The predicted versus observed plasma concentration-time profiles for alfentanil and lidocaine were similar, such that the pharmacokinetic changes associated with Child-Pugh class A, B and C liver cirrhosis were adequately described. The theophylline elimination half-life was greatly increased in Child-Pugh class B and C patients compared with controls, as predicted by the model. Levetiracetam urinary excretion was consistently reduced with disease progression and very closely resembled observed values.Conclusion: Consideration of the physiological differences between healthy individuals and patients with liver cirrhosis was important for the simulation of drug pharmacokinetics in this compromised group. The WB-PBPK model was altered to incorporate these physiological differences with the result of adequate simulation of drug pharmacokinetics. The information provided in this study will allow other researchers to further validate this liver cirrhosis model within a WB-PBPK model.