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

项目概要 对于复杂的药物产品（例如真皮药物）来说，只有很少的基因替代品 配方。这是因为建立皮肤科药物的生物等效性（BE） 通过进行比较临床终点研究的产品可能成本高昂，而且这些研究 可能不够灵敏，无法检测某些配方差异（Tsakalozou 等 2021）。建立计算机模型，例如基于生理学的药代动力学 (PBPK) 可能有助于创建替代 BE 路径，而无需严重依赖大型人类 临床研究。然而，这种 PBPK 模型的鲁棒性及其优势 回答系统充足性的监管问题（非药物相关） 向他们提供的信息。药物和制剂成分的相互作用 皮肤的成分（例如酶和蛋白质）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并且它们可能会有所不同 取决于皮肤状况（健康/疾病）以及在体内的位置和 人口的属性（年龄、种族等）。在这个项目中，主要酶 和人体皮肤的转运蛋白，与真皮的活性部分相关 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 学术界、工业界和 FDA 之间的合作取得了成果，并将解决 持续关注为透皮给药系统提供强大的计算机模型。 这些数据对于填充基于生理学的药代动力学 (PBPK) 是必要的 药物代谢和处置模型（包括但不限于那些由 人体皮肤的 Simcyp 模拟器）。目的是实现相关领域的广泛覆盖 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，目前公布的皮肤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。特别是我们 将解决潜在的种族差异，最初重点关注白人人口， 非洲-加勒比人。所有数据将用于填充 Simcyp MechaDema PBPK模型首次为制药业的实际应用创造一条直接途径 然而，数据将对所有参与 PBPK 的建模者开放。

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.