1. Population Pharmacokinetics of Levosimendan and its Metabolites in Critically Ill Neonates and Children Supported or Not by Extracorporeal Membrane Oxygenation.
- Author
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Bourgoin, Pierre, Lecomte, Jules, Oualha, Mehdi, Berthomieu, Lionel, Pereira, Tony, Davril, Emeline, Lamoureux, Fabien, Joram, Nicolas, Chenouard, Alexis, and Duflot, Thomas
- Subjects
EXTRACORPOREAL membrane oxygenation ,LEVOSIMENDAN ,CHILD support ,METABOLITES ,REMIFENTANIL ,VASODILATORS ,PHARMACOKINETICS ,CRITICALLY ill children ,PREMATURE infants - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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