Zhou Jie, Leonowens Cathrine, Ivaturi Vijay D, Lohmer Lauren L, Curd Laura, Ossig Joachim, Schippers Frank, Petersen Karl-Uwe, Stoehr Thomas, Schmith Virginia
Nuventra Pharma Sciences, Durham, NC, USA.
Center for Translational Medicine, University of Maryland School of Pharmacy Baltimore, USA.
J Clin Anesth. 2020 Nov;66:109899. doi: 10.1016/j.jclinane.2020.109899. Epub 2020 Jun 22.
To evaluate factors affecting variability in response to remimazolam in general anesthesia.
Plasma concentration-time data from 11 Phase 1-3 clinical trials were pooled for the population pharmacokinetic (popPK) analysis and concentration-bispectral index (BIS) data were pooled from 8 trials for popPK-PD analysis. A 3-compartment model with allometric exponents on clearance and volume described remimazolam concentrations over time. An effect compartment model with an inhibitory sigmoid Emax model was fit to the concentration-BIS data. Simulations were performed to assess sedation in general anesthesia and post-surgical sedation in healthy and sensitive populations.
General anesthesia and post-surgical sedation.
689 subjects included in popPK and 604 subjects included in popPK-PD. Most subjects (>85%) were ASA Class 1 or 2, with the remaining subjects being ASA Class 3.
Serial plasma concentrations and BIS scores.
Standard intra-operative monitoring.
PopPK model included an effect of extracorporeal circulation, ASA class, and sex on PK and a time-dependent clearance (~30% lower at 24 h) that was not related to cumulative dose. Co-administered remifentanil had a synergistic decrease in BIS with remimazolam. Remimazolam IC50 increased with cumulative dose. Onset was faster in overweight subjects and slower in Asian subjects. If using a weight-based regimen, simulations showed that remimazolam 6 mg/kg/h until loss of consciousness followed by 1 mg/kg/h during general anesthesia and 0.25 mg/kg/h for post-surgical sedation for up to 24 h is optimal, regardless of ASA class or sensitivity of subjects.
If using a weight-based regimen, results illustrated an appropriate regimen of remimazolam for general anesthesia and post-surgical sedation in general and sensitive populations, although lower doses can be considered in elderly patients with a significant disease burden or in ASA Class 3 patients. The time-dependent change in clearance is not clinically relevant for up to 24 h.
评估全身麻醉中影响瑞米唑仑反应变异性的因素。
将11项1-3期临床试验的血浆浓度-时间数据汇总用于群体药代动力学（popPK）分析，并将8项试验的浓度-脑电双频指数（BIS）数据汇总用于popPK-PD分析。用一个清除率和容积具有异速生长指数的三室模型来描述瑞米唑仑浓度随时间的变化。用一个具有抑制性S形Emax模型的效应室模型拟合浓度-BIS数据。进行模拟以评估健康人群和敏感人群在全身麻醉和术后镇静中的镇静效果。
全身麻醉和术后镇静。
popPK纳入689名受试者，popPK-PD纳入604名受试者。大多数受试者（>85%）为美国麻醉医师协会（ASA）1或2级，其余受试者为ASA 3级。
连续测定血浆浓度和BIS评分。
标准术中监测。
PopPK模型显示体外循环、ASA分级和性别对药代动力学有影响，且存在时间依赖性清除率（24小时时降低约30%），这与累积剂量无关。联合使用瑞芬太尼可使瑞米唑仑的BIS协同降低。瑞米唑仑的半数抑制浓度（IC50）随累积剂量增加。超重受试者起效更快，亚洲受试者起效更慢。模拟显示，如果采用基于体重的给药方案，无论受试者的ASA分级或敏感性如何，全身麻醉期间给予瑞米唑仑6mg/（kg·h）直至意识消失，随后给予1mg/（kg·h），术后镇静给予0.25mg/（kg·h）持续24小时是最佳方案。
如果采用基于体重的给药方案，研究结果表明了瑞米唑仑在一般人群和敏感人群全身麻醉和术后镇静中的合适给药方案，不过对于有重大疾病负担的老年患者或ASA 3级患者，可考虑较低剂量。清除率的时间依赖性变化在24小时内与临床无关。
