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

考虑群体变异性的虚拟生物等效性评估真皮 PBPK 建模平台的开发和验证

• 批准号: 9132016
• 负责人: Sebastian Polak
• 金额: $ 13.5万
• 依托单位: CERTARA UK LIMITED
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132016
• 关键词: Development; validation; dermal; PBPK; modelling

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.

项目总结/摘要 动物和人类数据之间的偶尔差异加上公众兴趣的增加， 减少研究中动物使用的法规要求，以及高成本和时间- 动物实验的消费属性推动了经济的发展， 可行且科学可靠的计算机模拟和体外方法，以评估皮肤药物吸收。 在其他建模方法中，基于生理学的药代动力学（PBPK）模型 具有独特的优势，因为它们分别考虑药物和制剂， 从潜在的生理特性及其变异性。因此，它们更好 能够预测群体的动力学，包括个体间变异性， 它们是一个强大的产品性能评估工具，从工业和监管 perspective. PBPK方法的另一个明显优势是， 外推一旦模型在一个群体中针对特定药物/制剂得到验证， 例如对于健康志愿者，可以对另一人群（如老年人）进行有把握的评估 提供了健康人和非健康人在人口统计学、解剖学和生理学上的差异， 老年人的特点很明显。Simcyp®基于人口的ADME模拟器提供 适用于各种PBPK模型的灵活且经过科学验证的算法，包括皮肤 吸收模块模拟器平台的开发主要侧重于临床 试验模拟在模拟过程中纳入个体间变异性，而不仅仅是 “普通人”，被大多数大型制药公司使用， 世界各地的监管机构。我们的目标是整合新的机制， 皮肤吸收中的重要作用，即皮肤表面pH、皮肤水合作用、皮肤 附属物，与角蛋白的结合，渗透性调节制剂成分的作用， 药物-生理学相互作用测量了厚度、脂质含量、pH值、水合作用等生理数据， 身体各部位皮肤毛囊的水平、微血管系统和密度，以促进健康 将收集、验证、分析志愿者、儿童、老年人和其他特殊人群 并纳入平台。此外，将提供深部组织隔室， 模拟药物渗透到皮下组织中，用于在作用部位局部作用药物 并将其与药效学模型相连接，以模拟药物作用。性能 将对所开发的模型和生理学进行验证，并将其分发给 科学界通过适当的渠道。