Colin Pieter J, Bichajian Lynn H, Curt Valentin R, Koomen Jeroen V, Stöhr Thomas, Struys Michel M R F, Mason Keira P
Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Eagle Pharmaceuticals Inc., Woodcliff Lake, New Jersey.
Anesthesiology. 2025 Aug 1;143(2):368-382. doi: 10.1097/ALN.0000000000005560. Epub 2025 May 12.
Remimazolam is not approved for use in pediatric patients. The pharmacokinetics of remimazolam have been reported to be similar to those of adult patients after scaling for body size. This article reports on the pharmacokinetics and pharmacodynamics of pediatric patients aged 6 to 18 yr and a subsequent model-based optimization of the used dosing regimen.
Thirty-one patients were included in the trial and stratified across four treatment arms: bolus administration, infusion, bolus plus fentanyl, or infusion plus fentanyl. The University of Michigan (Ann Arbor, Michigan) Sedation Scale (UMSS) was used to assess the depth of sedation. Blood samples were drawn to measure the concentrations of remimazolam and its metabolite CNS7054. Population pharmacokinetic pharmacodynamic modeling was performed in NONMEM (GloboMax LLC, USA).
A population pharmacokinetic model was developed for remimazolam and CNS7054. The elimination clearance of remimazolam was 0.70 l · min -1 · 70 kg -1 . A proportional odds model combined with a simplified Minto model described the observed UMSS well. The EC50 of remimazolam for a UMSS score of 3 or greater was 777 ng · ml -1 in the absence of fentanyl, and decreased to 655, 533, and 287 ng/ml for concomitant fentanyl steady state concentrations of 1, 2, or 4 ng · ml -1 , respectively. Simulations confirmed that the studied dosing regimen resulted in 9.2 to 22.0% of patients not reaching a UMSS score of 3 or greater at the end of the induction. Model-based optimization resulted in higher per-kilogram dosages and the removal of the maximum allowable dose. Simulations indicated that the percentage of patients achieving a UMSS score of 3 or greater can be expected to be high (88 to 97%).
This study has shown that the pharmacokinetics of remimazolam are likely different between children 6 yr or older and adults (after correcting for size). In addition, the exposure-response relationship shows that to effectively use remimazolam for procedural sedation in children 6 yr or older, the dosing regimen should be modified to allow for higher remimazolam exposures.
瑞马唑仑未被批准用于儿科患者。据报道，瑞马唑仑按体表面积校正后的药代动力学与成年患者相似。本文报道了6至18岁儿科患者的药代动力学和药效学，并基于模型对所用给药方案进行了优化。
31例患者纳入试验，分为四个治疗组：静脉推注、输注、静脉推注加芬太尼或输注加芬太尼。采用密歇根大学（密歇根州安阿伯）镇静评分量表（UMSS）评估镇静深度。采集血样以测定瑞马唑仑及其代谢产物CNS7054的浓度。在NONMEM（美国GloboMax LLC）中进行群体药代动力学药效学建模。
建立了瑞马唑仑和CNS7054的群体药代动力学模型。瑞马唑仑的清除率为0.70 l·min-1·70 kg-1。比例优势模型与简化的Minto模型相结合能很好地描述观察到的UMSS。在无芬太尼时，瑞马唑仑使UMSS评分为3或更高的半数有效浓度（EC50）为777 ng·ml-1，当芬太尼稳态浓度分别为1、2或4 ng·ml-1时，该EC50分别降至655、533和287 ng/ml。模拟结果证实，所研究的给药方案导致9.2%至22.0%的患者在诱导结束时未达到UMSS评分为3或更高。基于模型的优化导致每千克剂量更高且取消了最大允许剂量。模拟表明，达到UMSS评分为3或更高的患者百分比预计会很高（88%至97%）。
本研究表明，6岁及以上儿童与成人（校正体表面积后）的瑞马唑仑药代动力学可能不同。此外，暴露-反应关系表明，为有效使用瑞马唑仑对6岁及以上儿童进行程序性镇静，应调整给药方案以允许更高的瑞马唑仑暴露量。
