Physiology-Based Pharmacokinetics of Caspofungin for Adults and Paediatrics
Physiology-Based Pharmacokinetics of Caspofungin for Adults and Paediatrics
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DOI：
10.1007/s11095-014-1595-9
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发表时间：
2015-06
影响因子：
3.7
通讯作者：
Felix Stader;Gudrun Wuerthwein;A. Groll;J. Vehreschild;O. Cornely;G. Hempel
中科院分区：
文献类型：
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作者：
Felix Stader;Gudrun Wuerthwein;A. Groll;J. Vehreschild;O. Cornely;G. Hempel
目的卡泊芬净(CAS)是一种成人和儿童静脉应用的抗真菌药物。我们的目的是建立和验证基于生理学的药代动力学(PBPK)模型，以预测不同患者群体，特别是儿科患者的药代动力学。方法建立成人PBPK模型，并用CASLAMB和CASMTD两个临床试验的原始数据进行验证。结果PBPK模型的模拟结果与CASLAMB和CASMTD试验的观测值吻合较好。CASLAMB试验的患者接受CAS和环孢素A(CsA)的联合治疗，这可能是因为CsA抑制了肝脏运输蛋白OATP1B1，从而导致CAS的AUC0-24小时增加。然而，在PBPK模型中，CASLAMB和CASMTD患者之间OATP1B1的转运速率没有差异，提示CsA可能不影响OATP1B1。结论最终建立的不含个体化参数的PBPK模型能够准确预测不同患者群体的药代动力学。因此，该模型为研究人员选择婴幼儿等特殊人群的剂量和采样时间提供了依据。
PurposeCaspofungin (CAS) is an antifungal agent for intravenous application in adults and children. Our aim was the development and validation of a physiology-based pharmacokinetic (PBPK) model in order to predict the pharmacokinetics in different patient populations, particularly in paediatrics.MethodsA PBPK model for adults was built and validated with raw data of the two clinical trials CASLAMB and CASMTD. Afterwards, the model was scaled for paediatric patients under the consideration of known biochemical differences between adults and paediatrics.ResultsThe simulated results of the PBPK model were in good agreement with the observed values of the CASLAMB and CASMTD trial. Patients of the CASLAMB trial received CAS in combination with cyclosporine A (CsA), which leads to an increased AUC0–24hof CAS hypothetically due to an inhibition of the hepatic transport protein OATP1B1 by CsA. However, there was no difference in the transport rate of OATP1B1 between CASLAMB and CASMTD patients in the PBPK model, suggesting that CsA might not influence OATP1B1. Furthermore, the model was able to sufficiently predict the pharmacokinetics of paediatric patients compared to published data.ConclusionThe final PBPK model of CAS without individualized parameter is able to predict the pharmacokinetics in different patient populations correctly. Thus, the model provides a basis for investigators to choose doses and sampling times for special populations such as infants and small children.