Design, Development, Implementation and Validation of a Mechanistic Physiologically-based Pharmacokinetic (PBPK) Framework for the Prediction of the In Vivo Behaviour of Supersaturating Drug Products

用于预测过饱和药品体内行为的机械生理药代动力学 (PBPK) 框架的设计、开发、实施和验证

• 批准号: 9351280
• 负责人: David Barnes Turner
• 金额: $ 28.49万
• 依托单位: CERTARA UK LIMITED
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-10 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9351280
• 关键词: Design; Development; Implementation; Validation; Mechanistic

Project Summary / Abstract Physiologically-based pharmacokinetic (PBPK) models can separate drug/formulation characteristics from the underlying physiology and are well positioned to predict PK including inter-individual variability. A further advantage of Population PBPK is the ability to extrapolate from a model validated for a particular drug/formulation in one population (e.g., healthy volunteer) to another population (e.g., elderly or paediatric) provided the physiological differences are sufficiently well characterised. The Simcyp Population-Based Simulator includes a sophisticated oral absorption module which can simulate clinical trials predicting inter-individual variability rather than just an ‘average person’. This project aims to incorporate state-of-the art mechanistic models for handling supersaturation and precipitation (S&P) properties of poorly soluble drug products. S&P properties can have a major influence on the overall bioavailability of such compounds. Thus, the ability to anticipate these properties from in vitro experiments and extrapolate to in vivo outcomes can be critical to a drug development program; where appropriate formulation strategies can be followed to either prevent precipitation or mitigate its impact. The PBPK models require: drug and formulation-specific information; mechanistic algorithms for not only precipitation itself (such as, but not only, classical nucleation theory) but also the numerous other processes occurring within the gastrointestinal tract and the associated physiological and anatomical parameters and their inter-individual variability, which play an important role in supersaturation/precipitation behaviour in vivo. This includes gastric and small intestinal luminal fluid volumes; gastrointestinal transit times of fluids, fine particles and intact single unit dosage forms; regional luminal pH; fluid viscosity, effect of excipients, etc. The new mechanistic models are to be incorporated into both the Simcyp platform itself and crucially into separate complementary tools for modelling appropriate in vitro experiments such as media transfer experiments. This parallel implementation is essential for understanding, testing and parameterising the models. The existing standalone Simcyp In Vitro Analysis (SIVA) toolkit provides an ideal framework within which to add new modelling algorithms. At least eleven model drug products dosed under various conditions and exemplifying different mechanisms of supersaturation and precipitation are considered to be used for performance verification of the developed models and physiologies the results of which will be disseminated to the general scientific community through appropriate channels.

项目概要/摘要 基于生理学的药代动力学 (PBPK) 模型可以分离药物/制剂 基础生理学特征，可以很好地预测 PK，包括 个体间的变异性。群体 PBPK 的另一个优势是能够 从在一个人群中针对特定药物/制剂进行验证的模型进行推断（例如， 健康志愿者）向其他人群（例如老年人或儿童）提供 生理差异已得到充分表征。基于人口的 Simcyp 模拟器包括一个复杂的口服吸收模块，可以模拟临床试验 预测个体间的变异性而不仅仅是“普通人”。 该项目旨在整合最先进的机械模型来处理 难溶性药品的过饱和和沉淀 (S&P) 特性。标准普尔 性质可能对此类化合物的整体生物利用度产生重大影响。 因此，能够从体外实验中预测这些特性并推断出 体内结果对于药物开发计划至关重要；适当的配方 可以采取预防降水或减轻降水影响的策略。 PBPK 模型需要：药物和配方特定信息；机械算法不 不仅是沉淀本身（例如但不仅限于经典成核理论），而且还包括 胃肠道内发生的许多其他过程以及相关的 生理和解剖参数及其个体间差异， 在体内过饱和/沉淀行为中发挥重要作用。这包括胃和 小肠腔内液体量；液体、细颗粒和液体的胃肠道传输时间 完整的单一单位剂型；区域管腔 pH 值；流体粘度、赋形剂的影响等。 新的机械模型将被纳入 Simcyp 平台本身和 至关重要的是建立单独的补充工具来建模适当的体外实验 例如媒体传输实验。这种并行实施对于 理解、测试和参数化模型。现有的独立Simcyp In 体外分析 (SIVA) 工具包提供了一个理想的框架，可在其中添加新的建模 算法。至少十一种模型药品在不同条件下给药，并且 举例说明过饱和和沉淀的不同机制被认为是 用于开发模型和生理学结果的性能验证 将通过适当渠道向广大科学界传播。