根据监管指南，首次人体试验（FIH）剂量预测是临床开发的基本要素。人体起始剂量的选择是一个复杂的过程--它必须足够低以保证安全，但又必须足够高以避免剂量过度升级。药代动力学（PK）指导方法提供了更多的机理依据，可在 1 期研究之前对人体 PK 进行准确预测，从而大大节省成本和时间，最长可达6个月。基于生理学的药物动力学建模（PBPK）可用于药物发现和开发过程中的 PK 和剂量预测，适用于数据有限的先导药物开发之前的早期阶段，从而了解生理变量或疾病状态对 PK 的影响。
The Simcyp Approach for FIH
Initially, the PBPK simulation is performed in animals with Simcyp Animal™, using animal in vitro data and compound-specific physicochemical data. The animal simulation is compared with the in vivo data; if this simulation in animals is reasonable, then the human simulation is performed with the Simcyp Simulator™, using human in vitro data and compound-specific physicochemical data. If there are mismatches in animals then hypotheses/new data may be generated to explain the observations.
PBPK models incorporate physiology and mechanisms specific to the species of interest, allowing for prediction of multi-phasic profiles, increased understanding of characteristics of molecule and PK properties (driving factors for PK). Simcyp facilitates interspecies extrapolation and prediction for the many mechanisms that do not scale well allometrically.
A FIH PK prediction package as shown above uses readily available physiochemical, in vitro and pre-clinical in vivo input data. Add ons can include early drug-drug interactions (DDI) prediction and formulation comparisons. The types of questions that can be answered at this stage with PBPK modelling are shown below.
Applications for Simcyp (PBPK) in FIH and Discovery and Pre-clinical Development
- What is the predicted FIH PK and dose?
- Can we use modelling to do some early formulation screening and development work?
- What is the predicted exposure in toxicology studies and how can it be enhanced using PBPK?
- Why do we have non-linear PK?
- What are the required laboratory objectives for a chemical series?
- Which compound should move to the clinic?
- What is the predicted DDI liability?
- Do we expect time-dependent PK?
- What is the expected inter-individual variability?
- Do we expect an impact of genetic polymorphisms?
The Simcyp Simulator
Simcyp Simulator 是制药行业内最先进的生理药代动力学 (PBPK) 平台，用于确定首次人体用药、优化临床研究设计、评估新药配方、设定在未受测人群中使用的剂量、进行虚拟生物等效性分析及预测药物相互作用 (DDI)。Simcyp PBPK 模型描述了药物在不同人体组织中的行为，每个组织都被视为一个生理区室。通过组合系统数据、药物数据和试验设计信息来确定每个隔室中的药物浓度。We combine in vitro-in vivo extrapolation (IVIVE) and PBPK approaches in virtual individuals to predict drug concentration and effect.
