Department of Neonatal and Paediatric Intensive Care, Division of Paediatric Intensive Care, Erasmus MC-Sophia Children's Hospital, Room Sp-3435, Wytemaweg 80, 3015GD, Rotterdam, The Netherlands.
Rotterdam Clinical Pharmacometrics Group, Erasmus MC, Rotterdam, The Netherlands.
Clin Pharmacokinet. 2023 Jul;62(7):1011-1022. doi: 10.1007/s40262-023-01249-z. Epub 2023 May 29.
Pentobarbital pharmacokinetics (PK) remain elusive and the therapeutic windows narrow. Administration is frequent in critically ill children with refractory status epilepticus (SE) and severe traumatic brain injury (sTBI).
To investigate pentobarbital PK in SE and sTBI patients admitted to the paediatric intensive care unit (PICU) with population-based PK (PopPK) modelling and dosing simulations.
Develop a PopPK model with non-linear mixed-effects modelling (NONMEM) with retrospective data (n = 36; median age 1.3 years; median weight 10 kg; 178 blood samples) treated with continuous intravenous pentobarbital. An independent dataset was used for external validation (n = 9). Dosing simulations with the validated model evaluated dosing regimens.
A one-compartment PK model with allometrically scaled weight on clearance (CL; 0.75) and volume of distribution (V; 1) captured data well. Typical CL and V values were 3.59 L/70 kg/h and 142 L/70 kg, respectively. Elevated creatinine and C-reactive protein (CRP) levels significantly correlated to decreased CL, explaining 84% of inter-patient variability, and were incorporated in the final model. External validation using stratified visual predictive checks showed good results. Simulations demonstrated patients with elevated serum creatinine and CRP failed to achieve steady state yet progressed to toxic levels with current dosing regimens.
The one-compartment PK model of intravenous pentobarbital described data well whereby serum creatinine and CRP significantly correlated with pentobarbital CL. Dosing simulations formulated adjusted dosing advice in patients with elevated creatinine and/or CRP. Prospective PK studies with pharmacodynamic endpoints, are imperative to optimise pentobarbital dosing in terms of safety and clinical efficacy in critically ill children.
戊巴比妥的药代动力学（PK）仍然难以捉摸，治疗窗狭窄。在患有难治性癫痫持续状态（SE）和严重创伤性脑损伤（sTBI）的危重症儿童中，戊巴比妥需要频繁给药。
通过基于人群的 PK（PopPK）建模和给药模拟，调查入住儿科重症监护病房（PICU）的 SE 和 sTBI 患者的戊巴比妥 PK。
使用非线性混合效应建模（NONMEM）对接受连续静脉注射戊巴比妥治疗的回顾性数据（n=36；中位年龄 1.3 岁；中位体重 10kg；178 个血样）进行 PopPK 模型开发。使用独立数据集进行外部验证（n=9）。使用验证后的模型进行给药模拟，评估给药方案。
一个具有按比例缩放清除率（CL；0.75）和分布容积（V；1）的单室 PK 模型很好地捕捉了数据。典型的 CL 和 V 值分别为 3.59 L/70kg/h 和 142 L/70kg。肌酐和 C 反应蛋白（CRP）水平升高与 CL 降低显著相关，解释了 84%的患者间变异性，并被纳入最终模型。使用分层可视化预测检查进行的外部验证显示出良好的结果。模拟表明，血清肌酐和 CRP 升高的患者未能达到稳态，但在当前给药方案下进展到毒性水平。
描述静脉注射戊巴比妥的单室 PK 模型很好地描述了数据，其中血清肌酐和 CRP 与戊巴比妥 CL 显著相关。在肌酐和/或 CRP 升高的患者中，模拟制定了调整后的给药建议。需要进行具有药效学终点的前瞻性 PK 研究，以优化危重症儿童的戊巴比妥安全性和临床疗效的给药。
