Clinical trial NCT06993584: Pharmacokinetic Modelling of Levosimendan in Adults
Official title: Pharmacokinetic Modelling of Levosimendan in Adults in Cardiogenic Shock With or Without Extracorporeal Membrane Oxygenation Support
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Cardiogenic Shock
Keywords: cardiogenic shock
levosimendan
pharmacokinetics
ECMO
extracorporeal membrane oxygenation
ECLS
Lead sponsor: University Hospital, Rouen
Sponsor class: OTHER
Collaborators: name: University Hospital, Lille
name: Amiens University Hospital, France
First posted: 2025-05-29
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients treated with Lévosimendan (LVSMD) as part of their usual care for cardiogenic shock (60 with extracorporeal membrane oxygenation (ECMO) and 40 without ECMO)

Brief summary: In the light of current knowledge of the PK of levosimendan and its use in ECMO weaning, deciphering the mechanisms of inter-individual variability in exposure and response to levosimendan appears essential in order to better stratify patients eligible or not for this therapy and to adapt the treatment of patients in cardiogenic shock, with or without ECMO support, accordingly. The aim of this project is to use an innovative pharmacokinetic modelling approach based on clinico-biological data to study the key factors that could contribute to treatment failure in cardiogenic shock and to integrate them quantitatively for dose individualisation. The aim of this project is to conduct a prospective, multicentre, observational, comparative analysis, with minimal risks and constraints, to determine the concentrations of levosimendan and its metabolites during patient management in order to develop a pharmacokinetic model.

Detailed description: Cardiogenic shock is a pathological condition characterised by cardiac failure inducing tissue hypoxia and organ hypoperfusion, which can lead to multiple organ failure and death. Extracorporeal membrane oxygenation (ECMO) is a circulatory support technique commonly used in the treatment of cardiogenic shock. This device reduces mortality in patients with refractory shock, i.e. those who do not respond, or only partially respond, to medical treatment including inotropic and vasopressor pharmacological support. ECMO is associated with significant pharmacokinetic (PK) changes related to volume of distribution (Vd) and clearance (CL), which may alter the efficacy of treatments. From a PK point of view, the addition of an extracorporeal circuit capable of sequestering and/or degrading drugs represents a challenge for dose adjustment. Levosimendan (LVSMD) is a drug authorised for the treatment of acute decompensated heart failure. It's a lipophilic drug (logP=2.16) and highly protein-bound (\>97%), two properties that favour its sequestration in the ECMO circuit \[2\]. This hypothesis is reinforced by the recent publication of a RIPH3 study evaluating the PK of levosimendan in neonates and children in intensive care, whether or not assisted by ECMO (NCT03681379, Bourgoin P, Duflot T, Clin Pharmacokinet). The rationale for this project is based on the following hypotheses: 1°) Beneficial effects on renal function, pulmonary congestion, physical capacity and cardiac output have been observed with levosimendan in the management of cardiogenic shock \[4\] 2°) The use of antibiotics could alter the metabolism of LVSMD leading to a defect in the synthesis of the active metabolite. 3°) LVSMD is beneficial during weaning from ECMO and the contradictions in previously published results \[5\] could be attributed to a reduced half-life of the drug and/or OR-1896 due to adsorption phenomena on the ECMO circuit making the treatment less effective.

Eligibility criteria: Inclusion Criteria:

* Patient between 18 and 75 years of age admitted to an intensive care unit,
* Weight ≥ 50 kg,
* Patient with cardiogenic shock defined by a SCAI stage C, D, or E score.
* The medical team plans to initiate LVSMD treatment as part of the management of cardiogenic shock, according to the recommendations in the Summary of Product Characteristics (SmPC),
* Expected life expectancy \> 48 hours,
* Patient affiliated with a social security scheme,
* Due to the life-threatening nature of cardiogenic shock, the patient or, where applicable, family members or trusted person are informed as soon as possible and their consent is requested for the possible continuation of this research. They may also object to the use of the patient's data (and blood samples) for this research.

Exclusion Criteria:

* Pregnant, childbearing, or breastfeeding women,
* Persons deprived of their liberty by an administrative or judicial decision, or persons placed under judicial protection/guardianship or curatorship.

Primary outcomes:
measure: Elimination Clearance of Levosimendan (LVSMD) in Adult Patients in Cardiogenic Shock with Extracorporeal Membrane Oxygenation (ECMO)
timeFrame: At enrollment visit, hour 1, 2 and 6 At hour 24, 26 and 32 after enrollment visit
Secondary outcomes:
measure: Success rate of weaning in the ECMO patient group
timeFrame: Hour 72 after enrollment visit
measure: Hemodynamic success rate in the group without extracorporeal membrane oxygenation (ECMO)
timeFrame: Hour 72 after enrollment visit
measure: Population-based pharmacokinetic model of LVSMD and its metabolites
timeFrame: Hours 48, 72, 96, 120, 144, 168, 336 and 504 after enrollment visit
measure: Influence of a change in intestinal microbiota on the conversion of levosimendan into its active metabolite
timeFrame: Two rectal swabs 24 hours apart, H0 and H24
Other outcomes:
Locations:
city: Amiens
country: France
facility: Cardio-Thoracic-Vascular Resuscitation Department, university Hospital of Amiens
city: Lille
country: France
facility: Anesthesia Clinic - Resuscitation, University Hospital of Lile
city: Rouen
country: France
facility: Anesthesia-Resuscitation Department, University Rouen Hospital
Study officials:
affiliation: pharmacology department, University Hospital of Rouen
name: Thomas TD DUFLOT, PharmD
role: STUDY_CHAIR
affiliation: anesthesiology, University Hospital of Rouen
name: Emmanuel BESNIER, MD, PHD
role: STUDY_CHAIR
References: