Pfizer Uses Model-Based Drug Development to Help Reduce Phase II Attrition Rates

Pfizer is committed to model-based drug development. “Phase II attrition needs to be tackled at the root causes—right from the selection of the biological target in early discovery,” says Dr. Piet van der Graaf, senior director, Pharmacometrics and Clinical Pharmacology at Pfizer. “We wanted to apply modeling and simulation in the earlier phases of drug research and bridge the gap between systems biology and pharmacokinetic-pharmacodynamic (PK/PD) modeling approaches.”

一些建模软件包的基于文本的接口可以使其难以构建和共享越来越复杂的模型。“我们必须用手写所有方程。随着我们的模型变大，有更多的方程式，并建立它们并确保单位的一致性变得非常艰苦，“Benson说。“此外，当我们需要与其他研究人员进行沟通时，他们的长期方程列表并不容易理解，特别是如果他们不是专家的建模者。”

项目通常需要重大的临床前实验室投资，以建立对方法的信心和随后的临床试验来验证假设。为避免在无法成功的项目或方法上花费数百万美元和多年的研究努力，辉瑞希望能够先识别和终止他们。

Pfizer has started to develop an integratedSystems Pharmacologyapproach in which researchers use tools such as MATLAB and SimBiology to model, simulate, and analyze biological systems in the earliest stages of discovery and throughout development.

研究人员构建系统药理学模型以回答有关给定途径的问题，例如哪种受体可能是最佳靶标，需要药物化合物的浓度来实现所需的抑制。

Sometimes the group bases the initial model on a published Systems Biology Markup Language (SBML) model, imported directly into SimBiology and other software tools.

They next perform sensitivity analysis to identify and rank the most important targets in the model, using simulation events to model the introduction of a particular drug into the system.

它们通过审查诊断图来可视化结果，包括具有和没有药物存在的时间课程地块。

Using visual interfaces, they share the model, the plots, and other simulation results with the project team for the drug, who provide parameter estimates or other input to further refine the model.

On one project, the team explored the effectiveness of using small interfering RNA (siRNA) to inhibit the IKK enzyme in the NF-kB pathway. After constructing and simulating a model with 26 species and 64 parameters, they found that the level of inhibition siRNA provided was not sufficient to achieve the needed result. Subsequent experimental results were consistent with this conclusion.

辉瑞公司目前正在组装一个系统的库，该系统药理学模型组件可以重复使用，以便使用PK和系统生物学模型进一步加速分析。