Global Clinical Pharmacology, Johnson & Johnson Pharmaceutical Research & Development, 3210 Merryfield Row, San Diego, CA 92121, USA.
Curr Pharm Biotechnol. 2012 Jun;13(7):1360-75. doi: 10.2174/138920112800624436.
Pharmacokinetic/pharmacodynamic (PK/PD) modeling & simulation (M&S) provides quantitative assessment of dose/exposure-response relationships with extensive applications at the late stage drug development as well as during regulatory decision making. However, at preclinical and early phase clinical drug development, the importance of PK/PD M&S has not been as widely recognized. We reviewed selected PK/PD M&S literatures in order to convey importance of M&S in these early development phases. We focused on the application of M&S to select and optimize lead candidates, the use of preclinical PK/PD data to project the range of clinical doses, and the development of comprehensive dose/exposure-response models that can be used to forecast the probability of achieving a target response based on Phase 1 safety, PK and biomarker information. We also reviewed several other M&S approaches that are often used in early drug development such as physiologically-based pharmacokinetic (PBPK) modeling, meta-analysis, PK-pharmacogenomics modeling, and etc. Our aims were to provide expert opinions on the practical utility of PK/PD model-based approaches that have positive impact on early decision-making with the goal of improving the success rate of early to late stage drug development.
药代动力学/药效动力学（PK/PD）建模与模拟（M&S）为剂量/暴露-反应关系提供了定量评估，在药物开发后期以及监管决策中有着广泛的应用。然而，在临床前和早期临床药物开发阶段，PK/PD M&S 的重要性尚未得到广泛认可。我们回顾了一些选定的 PK/PD M&S 文献，以传达 M&S 在这些早期开发阶段的重要性。我们重点介绍了 M&S 在选择和优化先导候选物中的应用，利用临床前 PK/PD 数据来预测临床剂量范围，以及开发综合剂量/暴露-反应模型，该模型可用于根据 I 期安全性、PK 和生物标志物信息预测达到目标反应的概率。我们还回顾了其他几种常用于早期药物开发的 M&S 方法，如基于生理的药代动力学（PBPK）建模、荟萃分析、PK-药物基因组学建模等。我们的目的是提供对基于 PK/PD 模型方法的实际应用的专家意见，这些方法对早期决策具有积极影响，旨在提高早期到后期药物开发的成功率。
