Data from: Rapid quantitative pharmacodynamic imaging by a novel method: theory, simulation testing and proof of principle

Pharmacological challenge imaging has mapped, but rarely quantified, the sensitivity of a biological system to a given drug. We describe a novel method called rapid quantitative pharmacodynamic imaging. This method combines pharmacokinetic-pharmacodynamic modeling, repeated small doses of a challenge drug over a short time scale, and functional imaging to rapidly provide quantitative estimates of drug sensitivity including EC50 (the concentration of drug that produces half the maximum possible effect). We first test the method with simulated data, assuming a typical sigmoidal dose-response curve and assuming imperfect imaging that includes artifactual baseline signal drift and random error. With these few assumptions, rapid quantitative pharmacodynamic imaging reliably estimates EC50 from the simulated data, except when noise overwhelms the drug effect or when the effect occurs only at high doses. In preliminary fMRI studies of primate brain using a dopamine agonist, the observed noise level is modest compared with observed drug effects, and a quantitative EC50 can be obtained from some regional time-signal curves. Taken together, these results suggest that research and clinical applications for rapid quantitative pharmacodynamic imaging are realistic.药物激发成像（Pharmacological challenge imaging）已可绘制生物系统对特定药物的敏感性图谱，但鲜有针对该敏感性的定量表征研究。本研究提出一种名为快速定量药效学成像（rapid quantitative pharmacodynamic imaging）的新型方法，该方法整合药代动力学-药效动力学模型、短时间尺度下重复给予小剂量激发药物与功能成像技术，可快速获取药物敏感性的定量评估结果，其中涵盖半数有效浓度（EC50，即产生50%最大效应时的药物浓度）。本研究首先基于模拟数据对该方法进行验证：假设存在典型的S型剂量反应曲线，且成像存在缺陷，包括人为引入的基线信号漂移与随机噪声。在上述少量假设条件下，快速定量药效学成像可从模拟数据中可靠估算EC50值，仅当噪声掩盖药物效应，或效应仅在高剂量下出现时例外。在使用多巴胺激动剂开展的灵长类动物大脑初步功能磁共振成像（functional magnetic resonance imaging, fMRI）研究中，观测到的噪声水平相较于药物效应相对适度，可从部分脑区的时间信号曲线中获取定量EC50值。综上，上述结果表明快速定量药效学成像的科研与临床应用具备现实可行性。