Continuous infusion of physostigmine in patients with perioperative septic shock: a pharmacokinetic/pharmacodynamic study with population pharmacokinetic modeling
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. Ph...
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| Main Authors: | , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2019
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| In: |
Biomedicine & pharmacotherapy
Year: 2019, Volume: 118 |
| ISSN: | 1950-6007 |
| DOI: | 10.1016/j.biopha.2019.109318 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1016/j.biopha.2019.109318
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| Author Notes: | Nadine Pinder, Johannes B. Zimmermann, Silke Gastine, Gudrun Würthwein, Georg Hempel, Thomas Bruckner, Torsten Hoppe-Tichy, Markus A. Weigand, Stefanie Swoboda |
| Summary: | 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. |
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| Item Description: | Gesehen am 07.11.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1950-6007 |
| DOI: | 10.1016/j.biopha.2019.109318 |