Development of physiologically based pharmacokinetic model to evaluate the relative systemic exposure to quetiapine after administration of IR and XR formulations to adults, children and adolescents
Development of physiologically based pharmacokinetic model to evaluate the relative systemic exposure to quetiapine after administration of IR and XR formulations to adults, children and adolescents
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DOI：
10.1002/bdd.1899
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发表时间：
2014-09-01
影响因子：
2.1
通讯作者：
Bui, Khanh H.
中科院分区：
文献类型：
--
作者：
Johnson, Trevor N.;Zhou, Diansong;Bui, Khanh H.
奎硫平是一种非典型的抗精神病药物，具有高渗透性，中等溶解性，被定义为生物制药分类系统II类化合物。奎硫平速释(IR)制剂的药代动力学(PK)已在成人和儿童中进行过研究，但奎硫平缓释(XR)制剂仅在成人中进行过。本研究的目的是使用基于生理学的药代动力学模型(PBPK)来定量预测XR制剂在儿童和青少年中的PK。采用学习和确认的方法，利用体外ADME和理化数据、成人奎硫平IR/XR的临床PK数据和儿童奎硫平IR的临床PK数据，建立PBPK模型。这些模型可以很好地预测抑制和诱导细胞色素P3A4对奎硫平的PK、儿童和成人的奎硫平IR的PK谱以及奎硫平XR的PK谱的影响。不同年龄组的AUC和C-max比值(儿童与成人)与观察到的比值基本一致。此外，PBPK模型预测，在每天服用一次XR配方或两次IR配方后，儿童和青少年可能会获得类似的暴露，每天的总剂量相似。这项研究的结果有助于指导儿科使用奎硫平XR制剂的给药方案。版权所有(C)2014 John Wiley&Sons，Ltd.
Quetiapine is an atypical antipsychotic drug with a high permeability, moderate solubility and defined as a Biopharmaceutics Classification System class ll compound. The pharmacokinetics (PK) of the quetiapine immediate-release (IR) formulation has been studied in both adults and children, but the quetiapine extended-release (XR) formulation has only been conducted in adults. The purpose of the current study was to use physiologically based pharmacokinetic modeling (PBPK) quantitatively to predict the PK of the XR formulation in children and adolescents. Using a learn and confirm' approach, PBPK models were developed employing in vitro ADME and physicochemical data, clinical PK data of quetiapine IR/XR in adults and clinical PK data of quetiapine IR in children. These models can predict well the effects of CYP3A4 inhibition and induction on the PK of quetiapine, the PK profile of quetiapine IR in children and adults, and the PK profile of quetiapine XR in adults. The AUC and C-max ratios (children vs adults) for the different age groups were in reasonable agreement with the observed ratios. In addition, the PBPK model predicted that children and adolescents are likely to achieve a similar exposure following administration of either the XR formulation once daily or the IR formulation twice daily at similar total daily doses. The results from the study can help inform dosing regimens in pediatrics using the quetiapine XR formulation. Copyright (c) 2014 John Wiley & Sons, Ltd.