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...
Gespeichert in:
| Hauptverfasser: | , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2019
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| In: |
Biomedicine & pharmacotherapy
Year: 2019, Jahrgang: 118 |
| ISSN: | 1950-6007 |
| DOI: | 10.1016/j.biopha.2019.109318 |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1016/j.biopha.2019.109318
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| Verfasserangaben: | Nadine Pinder, Johannes B. Zimmermann, Silke Gastine, Gudrun Würthwein, Georg Hempel, Thomas Bruckner, Torsten Hoppe-Tichy, Markus A. Weigand, Stefanie Swoboda |
MARC
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| 245 | 1 | 0 | |a Continuous infusion of physostigmine in patients with perioperative septic shock |b a pharmacokinetic/pharmacodynamic study with population pharmacokinetic modeling |c Nadine Pinder, Johannes B. Zimmermann, Silke Gastine, Gudrun Würthwein, Georg Hempel, Thomas Bruckner, Torsten Hoppe-Tichy, Markus A. Weigand, Stefanie Swoboda |
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| 520 | |a 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. | ||
| 650 | 4 | |a Anticholium | |
| 650 | 4 | |a Cholinergic anti-inflammatory pathway | |
| 650 | 4 | |a Cholinesterase inhibitor | |
| 650 | 4 | |a Critically ill patients | |
| 650 | 4 | |a Eseroline (CID: 119198) | |
| 650 | 4 | |a Physostigmine salicylate | |
| 650 | 4 | |a Physostigmine salicylate (CID: 657348) | |
| 650 | 4 | |a Steady state concentration | |
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| 700 | 1 | |a Würthwein, Gudrun |e VerfasserIn |4 aut | |
| 700 | 1 | |a Hempel, Georg |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Swoboda, Stefanie |d 1974- |e VerfasserIn |0 (DE-588)128401591 |0 (DE-627)372642896 |0 (DE-576)297124838 |4 aut | |
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