Development and validation of dermal PBPK modelling platform towards virtual bioequivalence assessment considering population variability

项目摘要/摘要 动物和人类数据之间的偶尔差异，加上公众兴趣的上升和 监管要求减少研究中的动物使用，并结合高成本和高时间- 动物实验的消费属性推动了经济的发展 在硅胶和体外评估皮肤药物吸收的方法中可行和科学可靠。 在其他建模方法中，基于生理的药代动力学(PBPK)模型 有一个独特的优势，那就是他们把药物和制剂分开考虑 从潜在的生理学和它的变异性的特征。因此，它们更好 定位为预测种群的动力学，包括个体间的可变性 它们将成为来自行业和监管部门的强大的产品性能评估工具 透视。PBPK方法的另一个公认优势是有可能 推论。一旦该模型针对某一人群中的特定药物/配方进行验证 例如健康的志愿者，可以有信心地为另一个人群进行评估，例如老年人 提供了健康人和健康人之间的人口学、解剖学和生理学差异 老年人口的特点很好。Simcyp®基于人口的ADME模拟器提供 灵活且经过科学验证的各种PBPK模型的算法，包括真皮 吸收模块。开发了以临床为主要研究对象的仿真平台 试验模拟在模拟过程中结合了个体间的可变性，而不仅仅是 “普通人”，被大多数大型制药公司和 世界各地的监管机构。我们的目标是纳入发挥作用的新机制 在皮肤吸收中的重要作用，即皮肤表面的pH值，皮肤的水合作用，皮肤 附属物与角蛋白的粘合、渗透性改变配方成分的影响和 药物与生理的相互作用。厚度、脂肪含量、pH、水合作用等生理指标 健康人皮肤毛囊水平、微血管和密度的研究 志愿者、儿科、老年病和其他特殊人群将被收集、核实、分析 并整合到平台中。此外，还将提供深层组织隔间，以 模拟药物对作用部位局部作用药物的皮下组织渗透 并将其与药效学模型相联系，模拟药物效应。演出 将对开发的模型和生理进行验证，并将其分发给 通过适当的渠道为普通科学界提供支持。

Project Summary/Abstract Occasional disparity between the animal and human data plus rising public interest and regulatory requirements to reduce animal usage in research combined with high cost and time- consuming attributes of animal experiments have fuelled the development of economically viable and scientifically reliable in silico and in vitro methods to assess dermal drug absorption. Among other modelling approaches physiologically based pharmacokinetic (PBPK) models have a unique advantage in that they consider separately the drug and the formulation characteristics from the underlying physiology and its variability. Hence, they are better positioned to predict the kinetics for a population including inter-individual variability allowing them to be a powerful product performance assessment tool from an industrial and regulatory perspective. The other perceived advantage of PBPK approach is the possibility of extrapolations. Once the model is validated for a particular drug/formulation in one population e.g. healthy volunteer, it can be assessed with confidence for another population e.g. elderly provided the demographical, anatomical, and physiological differences between healthy and elderly populations are well characterised. Simcyp® Population-Based ADME Simulator offers flexible and scientifically validated algorithms for various PBPK models including dermal absorption module. The simulator platform has been developed with a main focus on clinical trials simulation incorporating the inter-individual variability during simulations rather than just the ‘average person’ and is being used by most of the big pharmaceutical companies and regulatory agencies across the world. We aim to incorporate new mechanisms that play important roles in dermal absorption, namely, skin surface pH, dermal hydration, skin appendages, bonding to keratin, effect of permeability-modifying formulation ingredients and drug-physiology interactions. The physiology data such as thickness, lipid content pH, hydration level, microvasculature and density of hair follicles in skin from various parts of body for healthy volunteer, paediatric, geriatric and other special populations will be collected, verified, analysed and incorporated into the platform. Additionally a deep tissue compartment will be provided to simulate drug permeation into subcutaneous tissue for locally acting drugs at the site of action and link it to the pharmacodynamics model to simulate the drug effect. The performance verification of the developed model and physiology will be carried out and disseminated to the general scientific community through appropriate channels.