Otago Pharmacometrics Group, School of Pharmacy, University of Otago, Dunedin, New Zealand.
Br J Clin Pharmacol. 2021 Mar;87(3):1411-1421. doi: 10.1111/bcp.14541. Epub 2020 Sep 15.
Current pharmacokinetic-pharmacodynamic models describing the haemodynamic changes often do not include necessary feedback mechanisms. These models provide adequate description of current data but may fail to adequately extrapolate to additional scenarios. This study aims to develop a minimal model to describe the short-term changes of haemodynamics that can be used as the basis for model development by future researchers.
A minimal haemodynamic model was developed to describe the influence of drugs on blood pressure components. The model structure was defined based on known mechanisms and previously published models. The model was evaluated under 2 different simulation settings. The model parameters were calibrated to describe (without estimation) the haemodynamics of 2 antihypertensive drugs with data extracted from the literature. Structural identifiability analysis was done using various combinations of the observed variable.
The proposed model structure includes mean arterial pressure, heart rate and stroke volume and is composed of 4 states described by differential equations. Model evaluation showed flexibility in describing the haemodynamics at different target perturbations. Overlay plots of model predictions and literature data showed a good description without data fitting. The structural identifiability analysis revealed all model parameters and initial conditions were identifiable only when heart rate, mean arterial pressure and cardiac output were measured together.
A minimal model of the haemodynamic system was developed and evaluated. The model accounted for short-term haemodynamic feedback processes. We propose that this model can be used as the basis for future pharmacometric analyses of drugs acting on the haemodynamic system.
目前描述血流动力学变化的药代动力学-药效动力学模型通常不包括必要的反馈机制。这些模型对当前数据提供了充分的描述，但可能无法充分外推到其他情况。本研究旨在开发一个最小模型来描述血流动力学的短期变化，该模型可作为未来研究人员进行模型开发的基础。
开发了一个最小血流动力学模型来描述药物对血压成分的影响。该模型结构基于已知的机制和先前发表的模型进行定义。该模型在 2 种不同的模拟设置下进行了评估。使用从文献中提取的数据，通过校准模型参数来描述（无需估计）2 种降压药物的血流动力学。使用各种观察变量的组合进行了结构可识别性分析。
所提出的模型结构包括平均动脉压、心率和每搏量，由 4 个由微分方程描述的状态组成。模型评估表明，在不同的目标扰动下，该模型具有描述血流动力学的灵活性。模型预测与文献数据的叠加图显示，无需数据拟合即可很好地描述。结构可识别性分析表明，只有当心率、平均动脉压和心输出量同时测量时，才能识别出所有模型参数和初始条件。
开发并评估了一个血流动力学系统的最小模型。该模型考虑了短期血流动力学反馈过程。我们建议该模型可作为未来对作用于血流动力学系统的药物进行药物计量分析的基础。
