Merck Sharp & Dohme Corp., Oss, The Netherlands.
Br J Clin Pharmacol. 2011 Sep;72(3):415-33. doi: 10.1111/j.1365-2125.2011.04000.x.
An integrated population pharmacokinetic-pharmacodynamic model was developed with the following aims: to simultaneously describe pharmacokinetic behaviour of sugammadex and rocuronium; to establish the pharmacokinetic-pharmacodynamic model for rocuronium-induced neuromuscular blockade and reversal by sugammadex; to evaluate covariate effects; and to explore, by simulation, typical covariate effects on reversal time.
Data (n= 446) from eight sugammadex clinical studies covering men, women, non-Asians, Asians, paediatrics, adults and the elderly, with various degrees of renal impairment, were used. Modelling and simulation techniques based on physiological principles were applied to capture rocuronium and sugammadex pharmacokinetics and pharmacodynamics and to identify and quantify covariate effects.
Sugammadex pharmacokinetics were affected by renal function, bodyweight and race, and rocuronium pharmacokinetics were affected by age, renal function and race. Sevoflurane potentiated rocuronium-induced neuromuscular blockade. Posterior predictive checks and bootstrapping illustrated the accuracy and robustness of the model. External validation showed concordance between observed and predicted reversal times, but interindividual variability in reversal time was pronounced. Simulated reversal times in typical adults were 0.8, 1.5 and 1.4 min upon reversal with sugammadex 16 mg kg(-1) 3 min after rocuronium, sugammadex 4 mg kg(-1) during deep neuromuscular blockade and sugammadex 2 mg kg(-1) during moderate blockade, respectively. Simulations indicated that reversal times were faster in paediatric patients and slightly slower in elderly patients compared with adults. Renal function did not affect reversal time.
Simulations of the therapeutic dosing regimens demonstrated limited impact of age, renal function and sevoflurane use, as predicted reversal time in typical subjects was always <2 min.
开发了一个综合的群体药代动力学-药效学模型，目的如下：同时描述舒更葡糖钠和罗库溴铵的药代动力学行为；建立罗库溴铵诱导的神经肌肉阻滞和舒更葡糖钠逆转的药代动力学-药效学模型；评估协变量的影响；并通过模拟探索典型协变量对逆转时间的影响。
使用了来自八项舒更葡糖钠临床研究的数据（n=446），涵盖了男性、女性、非亚洲人、亚洲人、儿科、成人和老年人，以及不同程度的肾功能损害。基于生理原理的建模和模拟技术用于捕捉罗库溴铵和舒更葡糖钠的药代动力学和药效学，并识别和量化协变量的影响。
舒更葡糖钠的药代动力学受肾功能、体重和种族的影响，罗库溴铵的药代动力学受年龄、肾功能和种族的影响。七氟醚增强了罗库溴铵诱导的神经肌肉阻滞。后验预测检查和自举法表明了模型的准确性和稳健性。外部验证表明观察到的和预测的逆转时间之间存在一致性，但逆转时间的个体间变异性很大。模拟典型成年人在罗库溴铵后 3 分钟给予舒更葡糖钠 16 mg/kg-1 时、在深度神经肌肉阻滞时给予舒更葡糖钠 4 mg/kg-1 时和在中度阻滞时给予舒更葡糖钠 2 mg/kg-1 时的逆转时间分别为 0.8、1.5 和 1.4 分钟。模拟结果表明，与成年人相比，儿科患者的逆转时间更快，老年患者的逆转时间略慢。肾功能不影响逆转时间。
治疗剂量方案的模拟表明，年龄、肾功能和七氟醚的使用影响有限，因为典型患者的预测逆转时间始终<2 分钟。
