Dermal Drug Product Quality and Bioequivalence Assessment through Advanced MAM and PBPK Simulation

摘要-经皮给药制剂质量和生物等效性评估 高级MAM和PBPK模拟 仿制药办公室（OGD）的任务是审查申办者的皮肤 声称与相同活性物质的参比上市产品具有生物等效性的剂型 剂型。赞助商需要有高度的信心，他们提交的申请， 被认为是生物等效的剂型将受到好评。的软件 实现基于生理学的药代动力学（PBPK）和机械吸收 模型（MAM），并考虑制剂在预测局部药物浓度中的作用， 皮肤和体循环都可以是减少时间和费用的有用工具 参与设计新的通用制剂，评估其生物等效性的潜力， 目前批准的剂型由行业和监管科学家。 拟议的项目将推进皮肤MAM/PBPK建模的最新技术， 经皮隔室吸收和转运（TCAT™）MAM/PBPK模型 GastroPlus®和MembranePlusTM软件应用程序， 描述（i）药物热力学活性和运输的时间演变， 制剂，因为它们的组分被吸收到皮肤中或蒸发损失;和（ii）正常 和病理皮肤生理学;特别是当它们涉及经皮渗透时。 具体而言，我们寻求增加药物和前药的主动代谢和转运模型， 与黑色素和角蛋白结合，以及通过制剂赋形剂增强药物渗透 （化学渗透增强）。新的制剂类型（例如固体脂质纳米颗粒和 纳米结构脂质载体）也将被添加到TCAT™模型中。最后，虚拟 将扩展GastroPlus®中的生物等效性模拟器，以更全面地反映 制剂变异性和皮肤生理变异性，并纳入生物等效性 基于局部皮肤浓度和全身浓度的制剂比较 浓度的 推进皮肤MAM和PBPK模拟的最新技术水平需要全面的 知识库作为科学基础，有才华的科学家可以应用， 开发适用于软件的有用公式和逻辑;高级计算机编程技能 将方程式和逻辑编码到软件中;经验丰富的科学家进行测试，验证， 文档，并支持软件的通用性。 在这些努力中，我们将与FDA和我们的合作伙伴保持密切联系。 合作伙伴，以确保项目团队专注于所需的软件开发 用于实施皮肤产品质量设计（QbD）和虚拟生物等效性 根据项目范围进行评估。

Abstract - Dermal Drug Product Quality and Bioequivalence Assessment Through Advanced MAM and PBPK Simulation The Office of Generic Drugs (OGD) is tasked with reviewing sponsor applications for dermal dosage forms that purport to be bioequivalent to reference listed products for the same active dosage forms. Sponsors need to have high confidence that the applications they submit for dosage forms which are thought to be bioequivalent will receive favorable reviews. Software that implements physiologically based pharmacokinetics (PBPK) and mechanistic absorption modeling (MAM), and accounts for formulation effects in predicting local drug concentrations in both the skin and systemic circulation can be a useful tool in reducing the time and expense involved in designing new generic formulations by assessing their potential to be bioequivalent to currently approved dosage forms by industry and regulatory scientists. The proposed project will advance the state-of-the-art for dermal MAM/PBPK modeling in the Transdermal Compartmental Absorption and Transit (TCAT™) MAM/PBPK model within the GastroPlus® and MembranePlusTM software applications by incorporating more detailed descriptions of (i) the temporal evolution of drug thermodynamic activity and transport in formulations as their components are absorbed into the skin or lost to evaporation; and (ii) normal and pathological skin physiologies; particularly as they relate to percutaneous permeation. Specifically, we seek to add models for active metabolism and transport of drugs and pro-drugs, binding to melanin and keratin, and enhancement of drug permeation by a formulation excipient (chemical permeation enhancement). New formulation types (e.g. solid lipid nanoparticles and nanostructured lipid carriers) will also be added to the TCAT™ model. Finally, the virtual bioequivalence simulator in GastroPlus® will be expanded to more comprehensively reflect formulation variability and skin physiological variability, and to include bioequivalence comparisons of formulations based on local skin concentrations in addition to systemic concentrations. Advancing the state-of-the-art for dermal MAM and PBPK simulation requires a comprehensive knowledge base to serve as the scientific foundation that talented scientists can apply in order to develop useful equations and logic suitable for software; high-level computer programming skills to encode the equations and logic into the software; and experienced scientists to test, validate, document, and support the software for general use. Throughout these efforts, we will maintain close contact with both the FDA and our collaboration partners in order to ensure that the project team focuses on the software developments needed for implementation of dermal product Quality by Design (QbD) and virtual bioequivalence assessments according to the scope of the project.