Population Pharmacokinetics of Levosimendan and its Metabolites OR-1855 and OR-1896 in Critically Ill Adults, Neonates and Infants on Veno-Arterial ECMO

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BACKGROUND AND OBJECTIVE: Levosimendan is an inotrope and vasodilator agent commonly used in critical care, particularly to facilitate weaning from veno-arterial extracorporeal membrane oxygenation (VA-ECMO). However, critical illness and ECMO may affect levosimendan and its clinically relevant metabolites' pharmacokinetics, potentially compromising circulating exposure and efficacy. There are limited data on levosimendan pharmacokinetics in critically ill patients, including those on VA-ECMO, thus emphasising the need for further research in this area. The aim of this study was to characterise the pharmacokinetic profile of levosimendan and its metabolites OR-1855 and OR-1896 in both critically ill adults and neonates/infants on VA-ECMO. METHODS: We conducted a bicentric, prospective, observational, pharmacokinetic study in critically ill adults and neonates/infants on VA-ECMO receiving levosimendan. Dosage history, sampling and clinical information were gathered. Samples were analysed by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry using a validated highly sensitive method. A population pharmacokinetic model describing levosimendan and its metabolites OR-1855 (inactive) and OR-1896 (active, long-lasting) was developed using non-linear mixed-effects modelling (NONMEM). Model-based simulations were performed to compare exposures produced by various dosing scenarios. RESULTS: Twenty-one patients, 15 adults, three neonates and three infants, provided 155 blood samples. In adults, levosimendan was started at a rate of 0.05 µg/kg/min for 1-4 h, then increased to maintenance doses reaching 0.1 (n = 9), 0.15 (n = 3) or 0.2 (n = 3) µg/kg/min for a total infusion time of approximately 24 h. The neonates/infants received a continuous infusion of 0.1 µg/kg/min for 48 h. A two-compartment model best characterised levosimendan pharmacokinetics, with a transit compartment adequately describing the metabolites' delayed synthesis. The transformation of OR-1855 into OR-1896 was 3.7-fold slower in neonates/infants than in adults. Model-based simulations using a standard 0.1-µg/kg/min regimen for 24 and 48 h in adults and neonates/infants, respectively, achieved lower levosimendan and metabolite concentrations in neonates/infants. Simulations using a 48-h infusion of 0.2 µg/kg/min in neonates/infants predict levosimendan concentrations comparable to those in adults receiving a 0.1-µg/kg/min maintenance dose. However, in this scenario, OR-1896 concentrations would remain considerably lower than in adults. CONCLUSIONS: Our data indicate that levosimendan and its metabolites exhibit altered the pharmacokinetics in neonates/infants on VA-ECMO. Although some of these changes may be associated with ECMO, definitive conclusions on causality cannot be drawn, as age-dependent specific physiology and critically ill conditions may also contribute. These findings support the consideration of dose optimisation in this population. In adults, levosimendan pharmacokinetics seem unaffected, although metabolite concentrations appear slightly reduced compared with non-critically ill patients with heart failure.

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