Development of a permeability-limited model of the human brain and cerebrospinal fluid (CSF) to integrate known physiological and biological knowledge: Estimating time varying CSF drug concentrations and their variability using invitro data.
Development of a permeability-limited model of the human brain and cerebrospinal fluid (CSF) to integrate known physiological and biological knowledge: Estimating time varying CSF drug concentrations and their variability using invitro data.
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DOI：
10.1016/j.dmpk.2016.03.005
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发表时间：
2016-06-01
影响因子：
2.1
通讯作者：
Jamei, Masoud
中科院分区：
文献类型：
--
作者：
Gaohua, Lu;Neuhoff, Sibylle;Jamei, Masoud
建立了由脑血液、脑质量、脑脊液和脑脊液组成的4室通透性受限脑(4Brain)模型，并将其纳入Simcyp模拟器中的基于生理的全身药代动力学(PBPK)模型中。描述了模型的假设条件、结构、控制方程和系统参数。该模型特别考虑了脑和脑脊液的解剖和生理，包括脑脊液的分泌、循环和吸收，以及存在于血脑屏障(BBB)和血脑脊液屏障(BCSFB)上的各种外流和摄取转运体的功能，以及已知的参数变异性。通过对扑热息痛和苯妥英钠的体外数据和临床观察，验证了模型的性能。模拟的扑热息痛脑脊液浓度与临床腰椎脑脊液静脉和口服剂量的数据相当。在考虑了疾病诱导的外排转运体在血脑屏障内的过度表达后，模拟了癫痫患者的苯妥英脑脊液浓度-时间曲线。各种假设情景，包括模型的特定药物和系统参数的变化，表明4Brain模型能够模拟转运体介导的药物-药物相互作用、腰椎穿刺术过程以及脑脊液周转率随年龄的变化对脑内局部PK的可能影响。
A 4-compartment permeability-limited brain (4Brain) model consisting of brain blood, brain mass, cranial and spinal cerebrospinal fluid (CSF) compartments has been developed and incorporated into a whole body physiologically-based pharmacokinetic (PBPK) model within the Simcyp Simulator. The model assumptions, structure, governing equations and system parameters are described. The model in particular considers the anatomy and physiology of the brain and CSF, including CSF secretion, circulation and absorption, as well as the function of various efflux and uptake transporters existing on the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), together with the known parameter variability. The model performance was verified using invitro data and clinical observations for paracetamol and phenytoin. The simulated paracetamol spinal CSF concentration is comparable with clinical lumbar CSF data for both intravenous and oral doses. Phenytoin CSF concentration-time profiles in epileptic patients were simulated after accounting for disease-induced over-expression of efflux transporters within the BBB. Various 'what-if' scenarios, involving variation of specific drug and system parameters of the model, demonstrated that the 4Brain model is able to simulate the possible impact of transporter-mediated drug-drug interactions, the lumbar puncture process and the age-dependent change in the CSF turnover rate on the local PK within the brain.