Quantitative Expression and Inter-Individual Variability of Skin Proteins Involved in Drug and Excipient Metabolism and Transporters Using Targeted and Label Free LC MS/MS Proteomics

使用靶向和无标记 LC MS/MS 蛋白质组学对参与药物和赋形剂代谢和转运蛋白的皮肤蛋白进行定量表达和个体间变异

• 批准号: 10372447
• 负责人: Jill Barber
• 金额: $ 29.64万
• 依托单位: UNIVERSITY OF MANCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2024-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372447
• 关键词: Quantitative; Expression; Inter; Individual; Variability

Project summary There are only few genetic alternatives for complex drug products such as the dermal formulations. This is because establishing bioequivalence (BE) for dermatological drug products by conducting comparative clinical endpoint studies can be costly and the studies may not be sufficiently sensitive to detect certain formulation differences (Tsakalozou et al 2021). Establishing in silico models such as physiologically-based pharmacokinetic (PBPK) might help with creation of alternative BE path without heavy reliance on large human clinical studies. However, robustness of such PBPK models and their advantages for answering the regulatory questions relay of sufficiency of system (non-drug-related) information supplied to them. The interaction of drug and formulation ingredients with the constituents of the skin (such as enzymes and proteins) determines the fate of the drug and exertion of its therapeutic effects. These might be highly non-linear and they may vary depending on the condition of the skin (health/disease) as well as location in the body and the attributes of the population (age, ethnicity etc). In this project, the principal enzymes and transporters of the human skin, which are relevant to both active moiety of dermal products as well as the ingredients in the formulation, will be quantified using variety of high resolution tandem mass spectrometry based proteomics measurements. This will be achieved by a collaboration between academia, industry and the FDA and will address the ongoing interest in providing robust in silico models for transdermal drug delivery systems. These data are necessary for populating physiologically based pharmacokinetic (PBPK) models of drug metabolism and disposition (including but not limited to those housed by the Simcyp Simulator) of human skin. The aim is to achieve very broad coverage of relevant proteins and, to this end, a global proteomic approach will be adopted. Proteomic studies are labour intensive and the current published data on skin is limited to few samples. We increase this to over 100 and attempt to stratify based on various attributes. In particular we will address potential ethnic differences focussing initially on Caucasian population and African-Caribbean individuals. All data will be used to populate the Simcyp MechaDema PBPK model in first instance to create an immediate path for practical use by pharmaceutical scientists however the data will remain open for all modellers engaged with PBPK.

项目摘要 对于复杂的药物产品，如真皮，只有很少的基因替代品。 制剂。这是因为建立皮肤科药物的生物等效性（BE） 产品进行比较临床终点研究可能是昂贵的， 可能不足以灵敏地检测某些制剂差异（Tsakalozou等人 2021年）。建立计算机模拟模型，如生理药代动力学（PBPK） 可能有助于创建替代BE路径，而无需严重依赖大型人力资源 临床研究。然而，这种PBPK模型的鲁棒性和它们对于 回答系统充分性的监管问题中继（非药物相关） 提供给他们的信息。药物和制剂成分与药物的相互作用 皮肤的成分（如酶和蛋白质）决定了药物的命运， 发挥其治疗作用。这些可能是高度非线性的， 取决于皮肤的状况（健康/疾病）以及在身体中的位置， 人口属性（年龄、种族等）。在这个项目中， 和人皮肤的转运蛋白，其与皮肤的活性部分和皮肤的活性部分相关。 产品以及配方中的成分，将使用各种高 基于分辨率串联质谱的蛋白质组学测量。这将是 通过学术界，工业界和FDA之间的合作实现，并将解决 持续的兴趣是为经皮给药系统提供稳健的计算机模型。 这些数据对于基于生理学的药代动力学（PBPK） 药物代谢和处置模型（包括但不限于 Simcyp模拟器）。目的是实现非常广泛的相关覆盖面， 蛋白质，并为此目的，将采用全球蛋白质组学方法。蛋白质组学研究 是劳动密集型的，并且目前公布的关于皮肤的数据仅限于少数样品。我们 将其增加到100以上，并尝试基于各种属性进行分层。我们尤其 将解决潜在的种族差异，首先关注高加索人群， 非洲裔加勒比人。所有数据将用于填充Simcyp MechaDema PBPK模型在第一个实例中创建一个直接的路径，供制药公司实际使用 然而，数据将对所有参与PBPK的建模者开放。