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

项目总结 对于复杂的药物产品，如真皮，只有很少的遗传替代品 配方。这是因为建立皮肤科药物的生物等效性(BE) 通过进行临床终点比较研究的产品成本可能很高，而且这些研究 可能不够敏感，无法检测到某些配方差异(Tsakalozou等人 2021年)。建立基于生理的药代动力学(PBPK)等计算机模型 可能有助于在不严重依赖大量人员的情况下创建替代BE路径 临床研究。然而，这种PBPK模型的稳健性及其对 回答监管问题传递系统的充分性(与毒品无关) 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)决定了药物的命运和 发挥其治疗作用。这些可能是高度非线性的，它们可能会有所不同 取决于皮肤的状况(健康/疾病)以及身体的位置和 人口的属性(年龄、种族等)。在这个项目中，主要的酶 和人体皮肤的转运蛋白，它们与真皮的活性部分有关 产品以及配方中的成分，将使用多种高 基于分辨率串联质谱仪的蛋白质组学测量。这将是 通过学术界、工业界和FDA的合作实现，并将解决 对为经皮给药系统提供可靠的电子计算机模型的兴趣持续存在。 这些数据对于推广基于生理的药代动力学(PBPK)是必要的 药物代谢和处置模型(包括但不限于 Simcyp模拟器)模拟人类皮肤。目标是实现非常广泛的相关覆盖范围 蛋白质，为此，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，目前公布的关于皮肤的数据仅限于少数样本。我们 将其增加到100以上，并尝试根据各种属性进行分层。尤其是我们 将首先解决潜在的种族差异，重点放在高加索人口和 非洲裔加勒比人。所有数据将用于填充Simcyp MechaDema 首推PBPK模式，为医药实用化创造立竿见影的路径 然而，科学家们将继续开放所有参与PBPK的模型师的数据。

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.