Pinder_2019_Biomed.Pharmacother_118_109318

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Title : Continuous infusion of physostigmine in patients with perioperative septic shock: A pharmacokinetic\/pharmacodynamic study with population pharmacokinetic modeling - Pinder_2019_Biomed.Pharmacother_118_109318
Author(s) : Pinder N , Zimmermann JB , Gastine S , Wurthwein G , Hempel G , Bruckner T , Hoppe-Tichy T , Weigand MA , Swoboda S
Ref : Biomed Pharmacother , 118 :109318 , 2019
Abstract :

BACKGROUND: In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium(R) 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 0.04mg/kg physostigmine salicylate, followed by continuous infusion of 1mg/h for up to 120h, 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+/-2.81ng/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 (EC50) of 5.99ng/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.

PubMedSearch : Pinder_2019_Biomed.Pharmacother_118_109318
PubMedID: 31398669

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Citations formats

Pinder N, Zimmermann JB, Gastine S, Wurthwein G, Hempel G, Bruckner T, Hoppe-Tichy T, Weigand MA, Swoboda S (2019)
Continuous infusion of physostigmine in patients with perioperative septic shock: A pharmacokinetic\/pharmacodynamic study with population pharmacokinetic modeling
Biomed Pharmacother 118 :109318

Pinder N, Zimmermann JB, Gastine S, Wurthwein G, Hempel G, Bruckner T, Hoppe-Tichy T, Weigand MA, Swoboda S (2019)
Biomed Pharmacother 118 :109318