术后脓毒性休克患者的毒扁豆碱持续输注：一项药代动力学/药效学研究及群体药代动力学建模。

Continuous infusion of physostigmine in patients with perioperative septic shock: A pharmacokinetic/pharmacodynamic study with population pharmacokinetic modeling.

机构信息

Pharmacy Department, Heidelberg University Hospital, Im Neuenheimer Feld 670, 69120 Heidelberg, Germany; Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.

Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.

出版信息

Biomed Pharmacother. 2019 Oct;118:109318. doi: 10.1016/j.biopha.2019.109318. Epub 2019 Aug 6.

DOI:10.1016/j.biopha.2019.109318

PMID:31398669

Abstract

BACKGROUND

In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive physostigmine salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting.

METHODS

In the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg physostigmine salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM.

RESULTS

Steady state physostigmine plasma concentrations reached 7.60 ± 2.81 ng/mL (mean ± standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%-50.6% of baseline activity during physostigmine salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by physostigmine, with an estimated half maximal effective concentration (EC) of 5.99 ng/mL.

CONCLUSIONS

PK of physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect.

摘要

背景

在胆碱能抗炎途径的背景下，临床试验 Anticholium® per Se（EudraCT 编号：2012-001650-26，ClinicalTrials.gov NCT03013322）探讨了在脓毒性休克中辅助使用毒扁豆碱水杨酸盐治疗的可能性，从理论研究到临床实践。药代动力学（PK）在危重病患者中可能发生改变；毒扁豆碱 PK 和靶浓度的数据很少，特别是对于连续输注。我们的目标是建立毒扁豆碱的群体 PK（popPK）模型，并进一步评估在此环境中的药效动力学（PD）和浓度-反应关系。

方法

在这项随机、双盲、安慰剂对照试验中，20 名围手术期脓毒性休克患者接受初始剂量 0.04mg/kg 毒扁豆碱水杨酸盐，随后以 1mg/h 的速度持续输注长达 120h，或接受等效体积的 0.9%氯化钠（安慰剂组）。测量毒扁豆碱血浆浓度和乙酰胆碱酯酶（AChE）活性；评估浓度-反应相关性，并使用 NONMEM 进行 popPK 和 PD 建模。

结果

稳态毒扁豆碱血浆浓度达到 7.60±2.81ng/mL（平均值±标准差[SD]）。PK 最好用具有线性清除率的两室模型来描述。清除率与体重和年龄有显著的协变量影响，以及中央分布容积的个体间变异性很高。在毒扁豆碱水杨酸盐输注期间，AChE 活性显著降低至基线活性的 30.5%-50.6%。毒扁豆碱对酶的抑制作用最好用 sigmoidal 直接效应 PD 模型来描述，其估计的半最大有效浓度（EC）为 5.99ng/mL。