Stéphane Bertin1, Monia Guidi1,2, David Haefliger1, Paul Thoueille1, Carine Bardinet1, Prof Laurent Arthur Decosterd3, Dr Maria-Helena Perez4, Dr Raphaël Giraud5, Dr Benjamin Assouline5, Dr Antoine Schneider6, Prof Thierry Buclin1, Dr Françoise Livio1
1Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne , 2Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, 3Laboratory of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, 4Pediatric Intensive and Intermediate Care Units, Lausanne University Hospital and University of Lausanne, 5Service of Intensive Care Medicine, Geneva University Hospitals, 6Adult Intensive Care Unit, Lausanne University Hospital and University of Lausanne
Introduction/Objectives Levosimendan is an inotrope and vasodilator agent commonly used in critical care, particularly to facilitate weaning from extracorporeal membrane oxygenation (ECMO). However, critical illness and ECMO may affect levosimendan and its clinically relevant metabolites’ pharmacokinetics (PK), potentially reducing drug exposure and compromising efficacy. There is limited data on levosimendan PK in critically ill patients, including those on ECMO, with only one population PK study in children [1] highlighting the need for further research in this area. This work aimed at characterising the PK of levosimendan and its metabolites OR-1855 (intermediate metabolite, inactive) and OR-1896 (active, equipotent) in critically ill patients on ECMO. Methods We conducted a bicentric prospective observational PK study in critically ill adults and children on ECMO receiving levosimendan. A population PK model describing levosimendan and its metabolites OR-1855 and long-lasting active OR-1896 was developed, using a classical stepwise approach (NONMEM). The allometric effect of body weight (BW) was included a priori on levosimendan clearance (CL) and central volume of distribution (V1) to account for physiological differences between adults and children. We tested different transit dispositions to best describe the slow apparition rate of metabolites assuming linear elimination for both with constant microconstants fixed at 0.01 h-1, according to their long elimination half-lives. Back-transformation from OR-1896 into OR-1855 (kM2-M1) was additionally investigated, fixing the value at 0.012 h-1 according to available information [2]. The following covariates were tested for significance on the base model parameters: BW, sex, age, height, population difference (child vs adult), glomerular filtration rate for patients not on continuous renal replacement therapy (CRRT), presence or absence of CRRT, albumin and bilirubin levels, ECMO flow rate, time since ECMO initiation, and number of comedications. A proportional error model was used for all compounds, with the likelihood method (M3) applied to model observations below the limit of quantitation [3–5]. Finally, model-based simulations were performed to compare exposures predicted under various dosing scenarios. Results Twenty-one patients, i.e. 15 adults and 6 children, provided 155 blood samples. In adults, levosimendan was started at a rate of 0.05 µg/kg/min for 1 to 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 hours. Children received a continuous infusion of 0.1 µg/kg/min for 48 hours. A two-compartment model (i.e., V1 and V2 for central and peripheral compartments, respectively) best characterised levosimendan PK, with one transit compartment adequately describing the metabolites’ delayed synthesis (ktransit). The transformation of OR-1855 into OR-1896 (kM2) was 3.7-fold slower in children than in adults. OR-1896 could undergo back-transformation into OR-1855 (kM2-M1). Final model parameters estimates with BSV (CV%) were: CL 13.9 L/h (32.4%), V1 15.9 L (51.5%), V2 5.75 L (99.1%), inter-compartmental clearance 0.5 L/h, ktransit 0.013 h-1 (37%), and kM2 0.072 h-1 (90.6%). Model-based simulations using a standard 0.1 µg/kg/min regimen for 24 h and 48 h in adults and children, respectively, achieved lower levosimendan and metabolites concentrations in children. Simulations using a 48 h-infusion of 0.2 µg/kg/min in children predict levosimendan concentrations comparable to those in adults receiving a 0.1 µg/kg/min maintenance dose. However, in this scenario, predicted OR-1896 concentrations remain considerably lower than in adults. Conclusions Our data indicate that levosimendan and its metabolites exhibit significantly impaired PK in children on ECMO, suggesting a need for dosage optimisation. In adults, levosimendan PK seem unaffected, although metabolites concentrations appear slightly reduced compared to non-critically ill patients with heart failure [6].
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Reference: PAGE 33 (2025) Abstr 11345 [www.page-meeting.org/?abstract=11345]
Poster: Drug/Disease Modelling - Other Topics