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.药物刺激成像（Pharmacological challenge imaging）虽已可绘制生物系统对特定药物的敏感性图谱，但极少能实现该敏感性的定量表征。本文提出一种名为快速定量药效成像（rapid quantitative pharmacodynamic imaging）的全新方法。该方法整合药代动力学-药效动力学（pharmacokinetic-pharmacodynamic）建模、短时间内重复给予小剂量刺激药物，以及功能成像技术，可快速获取药物敏感性的定量评估结果，其中包括半数效应浓度（EC50，即可产生50%最大效应的药物浓度）。本研究首先采用模拟数据对该方法进行验证，模拟场景采用典型的S型剂量-反应曲线，并假设成像存在缺陷，包含人为引入的基线信号漂移与随机误差。在上述少量假设条件下，快速定量药效成像可从模拟数据中可靠估算出EC50值，仅当噪声完全掩盖药物效应，或效应仅在高剂量下出现时例外。在针对灵长类大脑使用多巴胺激动剂的功能性磁共振成像（fMRI, functional magnetic resonance imaging）预实验中，观测到的噪声水平相较于药物效应处于适中水平，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，快速定量药效成像的科研与临床应用具备现实可行性。