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

项目总结/摘要 基于生理学的药代动力学（PBPK）模型可以将药物/制剂分开 基础生理学特征，并且能够很好地预测PK，包括 个体间变异性群体PBPK的另一个优点是能够 从对一个群体中的特定药物/制剂验证的模型外推（例如， 健康志愿者）到另一个群体（例如，老年人或儿童），前提是 生理差异被充分地表征。Simcyp基于人口的 模拟器包括一个复杂的口服吸收模块，可以模拟临床试验 预测个体间的差异，而不仅仅是一个“平均的人”。 该项目旨在将最先进的机械模型用于处理 过饱和和沉淀（S&P）性质的难溶性药物产品。S&P 这些性质对这些化合物的总体生物利用度具有主要影响。 因此，从体外实验中预测这些特性并外推到体外实验的能力是非常重要的。 体内结果对药物开发计划至关重要;适当时， 可以采取一些战略来防止降水或减轻其影响。的PBPK 模型需要：药物和配方特定信息; 不仅沉淀本身（例如，但不仅是经典的成核理论）， 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的变异性，这起着重要作用， 在体内过饱和/沉淀行为中的重要作用。这包括胃和 小肠腔液体体积;液体、细颗粒和 完整的单一单位剂型;局部管腔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， 重要的是，将其转化为单独的互补工具，用于模拟适当的体外实验 例如介质转移实验。这种并行实现对于 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，在其中添加新的建模 算法在各种条件下给药的至少11种模型制剂， 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的性能验证， 将通过适当渠道向广大科学界传播。

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.