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: 8925787
• 负责人: Sebastian Polak
• 金额: $ 13.04万
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925787
• 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.

项目概要/摘要 动物和人类数据之间偶尔存在差异，加上公众兴趣的提高和 减少研究中动物使用的监管要求以及高昂的成本和时间 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和体外方法来评估皮肤药物吸收。 除其他建模方法外，基于生理学的药代动力学 (PBPK) 模型 具有独特的优势，他们分别考虑药物和配方 因此，它们更好。 旨在预测群体的动力学，包括个体间的变异性，从而允许 它们将成为工业和监管部门强大的产品性能评估工具 PBPK 方法的另一个明显优势是可能性。 一旦模型在一个人群中针对特定药物/制剂得到验证。 例如健康志愿者，可以对其他人群（例如老年人）进行有信心的评估 提供了健康人和健康人之间的人口统计学、解剖学和生理学差异 Simcyp® 基于人口的 ADME 模拟器提供了对老年人群的详细描述。 适用于各种 PBPK 模型（包括真皮）的灵活且经过科学验证的算法 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结合了个体间的变异性，而不仅仅是 “普通人”，被大多数大型制药公司使用 我们的目标是整合发挥作用的新机制。 在真皮吸收中发挥重要作用，即皮肤表面pH值、真皮水合作用、皮肤 附属物、与角蛋白的结合、渗透性调节配方成分的影响以及 药物生理学相互作用。生理学数据，例如厚度、脂质含量、pH、水合作用。 身体各部位皮肤毛囊的水平、微血管和密度，以保证健康 志愿者、儿童、老年人等特殊人群将被收集、核实、分析 此外，还将提供一个深层组织隔室。 模拟药物渗透到皮下组织，使药物在作用部位局部发挥作用 并将其与药效模型联系起来，模拟药物作用。 将对开发的模型和生理学进行验证并分发给 一般科学界通过适当渠道。