Department of Clinical Pharmacology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Bispebjerg Bakke, Entrance 20C, 2nd floor, 2400, Copenhagen, Denmark.
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Clin Pharmacokinet. 2020 May;59(5):643-654. doi: 10.1007/s40262-019-00838-1.
Midazolam is a first-line drug for the treatment of status epilepticus, both by buccal and intravenous administration. In children and adolescents with obesity, midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient.
The objective of this study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese adolescents aged 11-18 years.
All trial participants received a 1-µg midazolam microdose as an intravenous bolus. 13 blood samples were collected per participant at pre-specified timepoints. Plasma concentration-time data were fitted to pharmacokinetic models using non-linear mixed-effects modeling. Covariates such as weight, age, and body mass index standard deviation score were tested to explain the inter-individual variability associated with the pharmacokinetic parameters.
Sixty-seven adolescents were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The rate of distribution was faster, and the peripheral volume of distribution was larger in adolescents with a high body mass index standard deviation score compared with adolescents with a lower standard deviation score. Simulations revealed that long-term infusions based on total body weight could lead to high plasma concentrations in adolescents with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose indicated that adolescents with obesity may be at risk of sub-therapeutic midazolam plasma concentrations.
The body mass index standard deviation score was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current dosing guidelines for status epilepticus, where the midazolam dose is adjusted to total body weight or age, may lead to supra- and sub-therapeutic plasma concentrations, respectively, in adolescents with obesity.
EudraCT: 2014-004554-34.
咪达唑仑是治疗癫痫持续状态的一线药物，无论是口腔内给药还是静脉内给药。在肥胖的儿童和青少年中，咪达唑仑的药代动力学可能会发生改变，因此目前的剂量指南可能不够充分。
本研究旨在研究静脉内给予咪达唑仑后肥胖和非肥胖青少年 11-18 岁患者的药代动力学。
所有试验参与者均接受 1μg 咪达唑仑微剂量静脉推注。每个参与者均按预定时间点采集 13 份血样。使用非线性混合效应模型对血浆浓度-时间数据进行拟合，以建立药代动力学模型。测试体重、年龄和体重指数标准差评分等协变量，以解释与药代动力学参数相关的个体间变异性。
共有 67 名青少年纳入分析。咪达唑仑的药代动力学最好用两室模型来描述。与低标准差评分的青少年相比，高体重指数标准差评分的青少年分布速度更快，外周分布容积更大。模拟结果表明，基于总体重的长期输注可能导致肥胖青少年的血浆浓度升高。此外，固定口腔剂量后的模拟血浆浓度表明肥胖青少年可能存在咪达唑仑血浆浓度低于治疗范围的风险。
体重指数标准差评分对咪达唑仑的外周分布容积和隔室间清除率有显著影响。目前治疗癫痫持续状态的剂量指南，根据总体重或年龄调整咪达唑仑剂量，可能分别导致肥胖青少年出现超治疗和低治疗血浆浓度。
EudraCT：2014-004554-34。
