Pharmacokinetic Tomography for the Measurement of Topical Drug Product Bioequivalence

项目摘要 缺乏准确和可靠的技术来可视化和量化传递和吸收 (药代动力学)小分子进入皮肤一直是开发这两种新药物的主要挑战 以及非专利外用药物。在生物等效性的测量中尤其如此，在这种情况下，仿制药 必须将候选药物与参考品牌药物进行比较。目前的方法依赖于昂贵的， 破坏性测量和整体测量不能提供提取所需的空间或时间分辨率 确定人体皮肤细胞水平药物随时间等效性的药代动力学曲线。新的 需要能够直接、实时、无创地量化人体药代动力学的工具 以推动局部药物领域的创新。 药物动力学断层成像(PKT)是一种生成各种不同类型药物的三维、实时地图的方法 使用光谱成像技术研究组织中的脂类、水、蛋白质和药物等分子物种。 这些成像技术利用药物分子的固有分子振动来跟踪它们的摄取。 不需要标记或改变分子结构。这项建议将发展出新的 相干拉曼成像工具为量化药物在体外人体皮肤中的行为创造了一个平台。 这个基于PKT的平台将能够测量药物的摄取，如抗生素、激酶抑制剂、 皮肤中的类固醇、维甲酸和非类固醇类药物具有亚细胞和亚秒级分辨率，可收集关键信息 药物开发和生物等效性测量所需的药代动力学参数。比较PKT的步骤 根据FDA认可的标准，这些PKT成像将与真皮开放血流一起进行 微灌注(Dofm)，一种皮肤液采样技术，测量药物随时间的浓度。这个 多模式PKT平台建成后，将能够现场测量各种药物的生物等效性 在人类实验对象中。 这项研究计划将专门开发新的成像工具包，将先进的显微镜和 最先进的计算机视觉和机器学习分析技术收集和提取药代动力学 数据。使用一种新型的多功能激光，我们将创造一种理想的相干拉曼技术来检测毒品 包含独特化学结构的分子。为了将该平台的适用性扩大到远距离 更广泛的潜在药物分子，我们将开发一种稀疏采样相干拉曼成像方法 这将通过其独特的分子结构组合来量化分子。

Project Summary The lack of accurate and reliable techniques for visualizing and quantifying the delivery and uptake (pharmacokinetics) of small molecules into the skin has been a major challenge in the development of both new and generic topical drugs. This is particularly true in the measurement of bioequivalence, where a generic drug candidate must be compared against a reference brand-label drug. Current methods, which rely on expensive, destructive, and bulk measurements do not provide the spatial or temporal resolution necessary to extract pharmacokinetic profiles to determine equivalence of drugs at the cellular level over time in human skin. New tools, which allow for direct, real-time quantification of pharmacokinetics non-invasively in humans are needed to drive innovation in the topical drug space. Pharmacokinetic Tomography (PKT) is a method of generated three-dimensional, real-time maps of various molecular species such as lipids, water, proteins and drugs in tissue using spectroscopic imaging techniques. These imaging techniques make use of the intrinsic molecular vibrations of drug molecules to track their uptake quantitatively without the need for labels or alterations to molecular structure. This proposal will develop new coherent Raman imaging tools to create a platform for quantifying the behavior of drugs in ex vivo human skin. This PKT-based platform will be able to measure the uptake of drugs such as antibiotics, kinase inhibitors, steroids, retinoids and NSAIDs in the skin with sub-cellular and sub-second time resolution to glean critical pharmacokinetic parameters needed for drug development and bioequivalence measurements. To compare PKT to an FDA-recognized standard, these PKT imaging will be carried out alongside dermal open flow microperfusion (dOFM), a skin fluid sampling technique that measures the concentration of drugs over time. The multimodal PKT platform, when completed, will be able to measure the bioequivalence of various drugs in situ in human subjects. This research program will specifically develop new imaging toolkits that combine advanced microscopy with state-of-the-art computer vision and machine learning analysis techniques to collect and extract pharmacokinetic data. Using a new type of versatile laser, we will create a coherent Raman technique ideal for detection of drug molecules which contain unique chemical structures. In order to broaden the applicability of the platform to a far wider range of potential drug molecules, we will develop a sparse sampling coherent Raman imaging approach that will quantify molecules by their unique combinations of molecular structures.