Department of Anesthesiology, Yokohama City University School of Medicine, Fukuura 3-9, Yokohama, Kanazawa-ku, 236-0004, Japan.
Department of Anesthesiology, Showa University School of Medicine, Tokyo, Japan.
J Anesth. 2022 Aug;36(4):493-505. doi: 10.1007/s00540-022-03079-y. Epub 2022 Jun 16.
Remimazolam besylate is a novel short-acting benzodiazepine. An appropriate pharmacokinetic model of remimazolam is desirable in anesthesia practice. The aim of the study was to develop a pharmacokinetic model using plasma samples from patients anesthetized with remimazolam. Influence of patient characteristics, context-sensitive decrement-times, and dose regimens were also examined.
Data were obtained from four trials on patients, and seven trials on healthy volunteers. The characteristics of 416 male and 246 female subjects were as follows: age, 18-93 years; body weight, 34-149 kg; and American Society of Anesthesiologists physical status (ASA-PS), I-IV. 2231 arterial and 3200 venous samples were used for the final model. The equilibration rate constant between arterial plasma and effect-site was estimated using the concept of time to peak effect. The final model was used to generate context-sensitive decrement times and dose regimens for general anesthesia.
A three-compartment model plus virtual venous compartment with allometric scaling of adjusted body weight (ABW), age, sex, and ASA-PS as covariates were selected as the final model. Elimination clearance was lower in males, and in subjects with higher ABW and ASA-PS scores. Approximately 10% or 20% higher dose rate was necessary in females than in males or ASA-PS I/II than III/IV patient. The context-sensitive half-time for effect-site concentration in a 55-year-old, 70-kg, 170-cm male or female ASA-PS I/II patient after > 6-h infusion was 16.7 or 15.9 min.
Remimazolam pharmacokinetic model for general anesthesia was successfully developed. ABW, ASA-PS, and sex has a considerable impact on the remimazolam concentration.
苯二氮䓬类药物盐酸瑞马唑仑是一种新型的短效苯二氮䓬类药物。在麻醉实践中，理想情况下需要建立一个合适的瑞马唑仑药代动力学模型。本研究旨在建立一个使用瑞马唑仑麻醉患者的血浆样本的药代动力学模型。同时还检查了患者特征、浓度时间依赖性半衰期和剂量方案的影响。
数据来自于四项针对患者的试验和七项针对健康志愿者的试验。416 名男性和 246 名女性患者的特征如下：年龄 18-93 岁；体重 34-149kg；美国麻醉医师协会身体状况评分（ASA-PS）I-IV 级。最终模型共使用了 2231 个动脉和 3200 个静脉样本。使用达峰效应时间的概念来估计动脉血浆与效应部位之间的平衡速率常数。最终模型用于生成全身麻醉的浓度时间依赖性半衰期和剂量方案。
选择三房室模型加虚拟静脉室，以调整后的体重（ABW）、年龄、性别和 ASA-PS 作为协变量，作为最终模型。男性清除率较低，ABW 和 ASA-PS 评分较高的患者清除率也较低。女性的剂量率比男性或 ASA-PS I/II 患者高约 10%或 20%。对于一名 55 岁、70kg、170cm 的男性或女性 ASA-PS I/II 患者，输注>6 小时后，效应部位浓度的浓度时间依赖性半衰期为 16.7 或 15.9 分钟。
成功建立了用于全身麻醉的瑞马唑仑药代动力学模型。ABW、ASA-PS 和性别对瑞马唑仑浓度有较大影响。
