Continuous infusion of physostigmine in patients with perioperative septic shock

• Verfasst von: Pinder, Nadine [VerfasserIn]
• Verfasst von: Zimmermann, Johannes B. [VerfasserIn]
• Verfasst von: Gastine, Silke [VerfasserIn]
• Verfasst von: Würthwein, Gudrun [VerfasserIn]
• Verfasst von: Hempel, Georg [VerfasserIn]
• Verfasst von: Bruckner, Thomas [VerfasserIn]
• Verfasst von: Hoppe-Tichy, Torsten [VerfasserIn]
• Verfasst von: Weigand, Markus A. [VerfasserIn]
• Verfasst von: Swoboda, Stefanie [VerfasserIn]
• Titel: Continuous infusion of physostigmine in patients with perioperative septic shock
• Titelzusatz: a pharmacokinetic/pharmacodynamic study with population pharmacokinetic modeling
• Verf.angabe: Nadine Pinder, Johannes B. Zimmermann, Silke Gastine, Gudrun Würthwein, Georg Hempel, Thomas Bruckner, Torsten Hoppe-Tichy, Markus A. Weigand, Stefanie Swoboda
• Jahr: 2019
• Umfang: 8 S.
• Fussnoten: Gesehen am 07.11.2019
• Titel Quelle: Enthalten in: Biomedicine & pharmacotherapy
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1989
• Jahr Quelle: 2019
• Band/Heft Quelle: 118(2019) Artikel-Nummer 109318, 8 Seiten
• ISSN Quelle: 1950-6007
• DOI: doi:10.1016/j.biopha.2019.109318
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Anticholium
• Sach-SW: Cholinergic anti-inflammatory pathway
• Sach-SW: Cholinesterase inhibitor
• Sach-SW: Critically ill patients
• Sach-SW: Eseroline (CID: 119198)
• Sach-SW: Physostigmine salicylate
• Sach-SW: Physostigmine salicylate (CID: 657348)
• Sach-SW: Steady state concentration
• K10plus-PPN: 1681414996

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 0.04mg/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.