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Population Pharmacokinetics of Levosimendan and its Metabolites in Critically Ill Neonates and Children Supported or Not by Extracorporeal Membrane Oxygenation

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A Correction to this article was published on 08 February 2023

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Abstract

Background

Levosimendan (LVSMD) is a calcium-sensitizer inotropic and vasodilator agent whose use might have a beneficial effect on the weaning of venoarterial extracorporeal membrane oxygenation (VA-ECMO). In light of LVSMD pharmacological characteristics, we hypothesized that ECMO may induce major pharmacokinetic (PK) modifications for LVSMD and its metabolites.

Objective

The aim of this study was to investigate the PK of LVSMD and its metabolites, and to assess the effects of ECMO on PK parameters.

Methods

We conducted a multicentric, prospective study (NCT03681379). Twenty-seven infusions of LVSMD were performed, allowing for the collection of 255 blood samples. Non-linear mixed-effects modeling software (MONOLIX®) was used to develop a parent-metabolite PK model of LVSMD and its metabolites.

Results

Most patients received a 0.2 µg/kg/min infusion of LVSMD over 24 h. After elimination of non-reliable samples or concentrations below the limit of quantification, 166, 101 and 85 samples were considered for LVSMD, OR-1855 and OR-1896, respectively, of which 81, 53 and 41, respectively, were drawn under ECMO conditions. Parent-metabolite PK modeling revealed that a two-compartment model with first-order elimination best described LVSMD PK. Use of a transit compartment allowed for an explanation of the delayed appearance of circulating OR-1855 and OR-1896, with the latter following a first-order elimination. Patient weight influenced the central volume of distribution and elimination of LVSMD. ECMO support increased the elimination rate of LVSMD by 78%, and ECMO also slowed down the metabolite formation rate by 85% for OR-1855, which in turn is converted to the active metabolite OR-1896, 14% slower than without ECMO. Simulated data revealed that standard dosing may not be appropriate for patients under ECMO, with a decrease in the steady-state concentration of LVSMD and lower exposure to the active metabolite OR-1896.

Conclusions

ECMO altered PK parameters for LVSMD and its metabolites. An infusion of LVSMD over 48 h, instead of 24 h, with a slightly higher dose may promote synthesis of the active metabolite OR-1896, which is responsible for the long-term efficacy of LVSMD. Further trials evaluating ECMO effects using a PK/pharmacodynamic approach may be of interest.

Registration: ClinicalTrials.gov identifier number NCT03681379.

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Acknowledgements

The authors are grateful to the technical staff of the Laboratory of Pharmacokinetics of Rouen University Hospital for their support, and to all the physician’s staff who helped collect blood samples during their night-shifts. PB warmly thanks Club ECMO Pediatrique, Arcothova, and Dr. Ph. Mauriat for his help. Finally, the authors are grateful to Mr and Mrs Fox for their help in editing the present manuscript.

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Authors and Affiliations

  1. Pediatric Intensive Care Unit, CHU Nantes, 44093, Nantes, France

    Pierre Bourgoin, Nicolas Joram & Alexis Chenouard

  2. Department of Anesthesiology, CHU Nantes, 44093, Nantes, France

    Pierre Bourgoin & Jules Lecomte

  3. Pediatric Intensive Care Unit, CHU Necker Enfants Malades, 75015, Paris, France

    Mehdi Oualha

  4. Pediatric Intensive Care Unit, CHU Toulouse, 31059, Toulouse, France

    Lionel Berthomieu

  5. INSERM U1096, UNIROUEN, Normandie University, 76000, Rouen, France

    Tony Pereira, Emeline Davril, Fabien Lamoureux & Thomas Duflot

  6. Department of Pharmacology, CHU Rouen, 76000, Rouen, France

    Fabien Lamoureux & Thomas Duflot

  7. CHU Rouen, CIC-CRB U1404, 76000, Rouen, France

    Thomas Duflot

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Correspondence to Pierre Bourgoin.

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Funding

No external funding was used in the preparation of this manuscript.

Conflicts of interest

Pierre Bourgoin’s institution received funding from Orion Pharma, Espoo, Finland. Jules Lecomte, Mehdi Oualha, Lionel Berthomieu, Tony Pereira, Emeline Davril, Fabien Lamoureux, Nicolas Joram, Alexis Chenouard, and Thomas Duflot declare they have no potential conflicts of interest.

Ethics approval

The study was approved by an independent review board (CPP IV Ile de France, reference 018-A02042-53). This study was conducted in accordance with the Helsinki Declaration.

Consent to participate

Parents provided written informed consent during the inclusion visit.

Consent for publication

Not applicable.

Code availability

Not applicable.

Data availability

All data generated or analyzed during this study are included in this published article and its online resources. Feel free to contact the corresponding author if needed.

Author contribution

PB and TD: Conceptualization, Data Curation, Analysis, Funding acquisition, Investigation, Writing, editing and Reviewing the manuscript. JL: Data curation, Analysis. MO, LB, NJ and AC: local investigators, Reviewing of the manuscript. TP, ED, FL: laboratory investigations.

Additional information

The original online version of this article was revised to correct the author name Mehdi Oualha.

Supplementary Information

The following information can be found in the Supplementary Information file available from the journal home page: S1, table: characteristics of patients supported with ECMO, S2, table: overview of BICc for various model tested,S3, figures a, b and c representing individual fits for LVSMD, OR-1855 and OR-1896 respectively, S4 and S5, csv file and word document: data available and list of abreviations, S6, figure: examples of clinical scenarios and corresponding modelizations (see text for details). Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 766 KB)

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Bourgoin, P., Lecomte, J., Oualha, M. et al. Population Pharmacokinetics of Levosimendan and its Metabolites in Critically Ill Neonates and Children Supported or Not by Extracorporeal Membrane Oxygenation. Clin Pharmacokinet 62, 335–348 (2023). https://doi.org/10.1007/s40262-022-01199-y

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