Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Br J Anaesth. 2017 Aug 1;119(2):211-220. doi: 10.1093/bja/aex086.
Dexmedetomidine, a selective α 2 -adrenoreceptor agonist, has unique characteristics, with little respiratory depression and rousability during sedations. We characterized the haemodynamic properties of dexmedetomidine by developing a pharmacokinetic-pharmacodynamic (PKPD) model with a focus on changes in mean arterial blood pressure (MAP) and heart rate.
Dexmedetomidine was delivered i.v. to 18 healthy volunteers in a step-up fashion by target-controlled infusion using the Dyck model. Exploratory PKPD modelling and covariate analysis were conducted in NONMEM.
Our model adequately describes dexmedetomidine-induced hypotension, hypertension, and bradycardia, with a greater effective concentration for the hypertensive effect. Changes in MAP were best described by a double-sigmoidal E max model with hysteresis. Covariate analysis revealed no significant covariates apart from age on the baseline MAP in the population pharmacokinetic model used to develop this PKPD model. Simulations revealed good general agreement with published descriptive studies of haemodynamics after dexmedetomedine infusion.
The present integrated PKPD model should allow tighter control over the desired level of sedation, while limiting potential haemodynamic side-effects.
NCT01879865.
右美托咪定是一种选择性α2-肾上腺素受体激动剂，具有独特的特性，在镇静过程中呼吸抑制和苏醒能力较小。我们通过建立一个以平均动脉压（MAP）和心率变化为重点的药代动力学-药效学（PKPD）模型来描述右美托咪定的血液动力学特性。
通过使用 Dyck 模型，通过目标控制输注以递增的方式向 18 名健康志愿者静脉给予右美托咪定。在 NONMEM 中进行探索性 PKPD 建模和协变量分析。
我们的模型充分描述了右美托咪定引起的低血压、高血压和心动过缓，并且对高血压效应的有效浓度更高。MAP 的变化最好通过具有滞后的双西格玛 E max 模型来描述。协变量分析除了人口药代动力学模型中基线 MAP 上的年龄外，未发现其他显著协变量。模拟结果显示，与右美托咪定输注后血液动力学描述性研究的良好总体一致性。
目前的综合 PKPD 模型应允许更严格地控制所需的镇静水平，同时限制潜在的血液动力学副作用。
NCT01879865。
