Stroh Mark, Addy Carol, Wu Yunhui, Stoch S Aubrey, Pourkavoos Nazaneen, Groff Michelle, Xu Yang, Wagner John, Gottesdiener Keith, Shadle Craig, Wang Hong, Manser Kimberly, Winchell Gregory A, Stone Julie A
Department of Clinical Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., WP75B-100, 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486-0004, USA.
AAPS J. 2009 Mar;11(1):99-108. doi: 10.1208/s12248-009-9083-6. Epub 2009 Feb 6.
We describe how modeling and simulation guided program decisions following a randomized placebo-controlled single-rising oral dose first-in-man trial of compound A where an undesired transient blood pressure (BP) elevation occurred in fasted healthy young adult males. We proposed a lumped-parameter pharmacokinetic-pharmacodynamic (PK/PD) model that captured important aspects of the BP homeostasis mechanism. Four conceptual units characterized the feedback PD model: a sinusoidal BP set point, an effect compartment, a linear effect model, and a system response. To explore approaches for minimizing the BP increase, we coupled the PD model to a modified PK model to guide oral controlled-release (CR) development. The proposed PK/PD model captured the central tendency of the observed data. The simulated BP response obtained with theoretical release rate profiles suggested some amelioration of the peak BP response with CR. This triggered subsequent CR formulation development; we used actual dissolution data from these candidate CR formulations in the PK/PD model to confirm a potential benefit in the peak BP response. Though this paradigm has yet to be tested in the clinic, our model-based approach provided a common rational framework to more fully utilize the limited available information for advancing the program.
我们描述了在化合物A的随机安慰剂对照单次递增口服剂量人体首次试验中，当禁食的健康年轻成年男性出现意外的短暂血压（BP）升高时，建模与模拟如何指导方案决策。我们提出了一个集总参数药代动力学-药效学（PK/PD）模型，该模型捕捉了血压稳态机制的重要方面。四个概念单元表征了反馈PD模型：一个正弦血压设定点、一个效应室、一个线性效应模型和一个系统响应。为了探索将血压升高降至最低的方法，我们将PD模型与一个改进的PK模型相结合，以指导口服控释（CR）制剂的开发。所提出的PK/PD模型捕捉到了观测数据的中心趋势。用理论释放速率曲线获得的模拟血压响应表明，CR可使血压峰值响应有所改善。这引发了后续CR制剂的开发；我们在PK/PD模型中使用了这些候选CR制剂的实际溶出数据，以确认对血压峰值响应的潜在益处。尽管这种模式尚未在临床中进行测试，但我们基于模型的方法提供了一个通用的合理框架，以便更充分地利用有限的可用信息来推进该方案。
