PMID- 36631687
OWN - NLM
STAT- MEDLINE
DCOM- 20230313
LR  - 20230511
IS  - 1179-1926 (Electronic)
IS  - 0312-5963 (Linking)
VI  - 62
IP  - 2
DP  - 2023 Feb
TI  - Population Pharmacokinetics of Levosimendan and its Metabolites in Critically Ill 
      Neonates and Children Supported or Not by Extracorporeal Membrane Oxygenation.
PG  - 335-348
LID - 10.1007/s40262-022-01199-y [doi]
AB  - 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(R)) was used to develop a 
      parent-metabolite PK model of LVSMD and its metabolites. RESULTS: Most patients 
      received a 0.2 microg/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.
CI  - (c) 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
FAU - Bourgoin, Pierre
AU  - Bourgoin P
AUID- ORCID: 0000-0001-7713-8153
AD  - Pediatric Intensive Care Unit, CHU Nantes, 44093, Nantes, France. 
      pierre.bourgoin@chu-nantes.fr.
AD  - Department of Anesthesiology, CHU Nantes, 44093, Nantes, France. 
      pierre.bourgoin@chu-nantes.fr.
FAU - Lecomte, Jules
AU  - Lecomte J
AD  - Department of Anesthesiology, CHU Nantes, 44093, Nantes, France.
FAU - Oualha, Mehdi
AU  - Oualha M
AD  - Pediatric Intensive Care Unit, CHU Necker Enfants Malades, 75015, Paris, France.
FAU - Berthomieu, Lionel
AU  - Berthomieu L
AD  - Pediatric Intensive Care Unit, CHU Toulouse, 31059, Toulouse, France.
FAU - Pereira, Tony
AU  - Pereira T
AD  - INSERM U1096, UNIROUEN, Normandie University, 76000, Rouen, France.
FAU - Davril, Emeline
AU  - Davril E
AD  - INSERM U1096, UNIROUEN, Normandie University, 76000, Rouen, France.
FAU - Lamoureux, Fabien
AU  - Lamoureux F
AD  - INSERM U1096, UNIROUEN, Normandie University, 76000, Rouen, France.
AD  - Department of Pharmacology, CHU Rouen, 76000, Rouen, France.
FAU - Joram, Nicolas
AU  - Joram N
AD  - Pediatric Intensive Care Unit, CHU Nantes, 44093, Nantes, France.
FAU - Chenouard, Alexis
AU  - Chenouard A
AD  - Pediatric Intensive Care Unit, CHU Nantes, 44093, Nantes, France.
FAU - Duflot, Thomas
AU  - Duflot T
AUID- ORCID: 0000-0002-8730-284X
AD  - INSERM U1096, UNIROUEN, Normandie University, 76000, Rouen, France.
AD  - Department of Pharmacology, CHU Rouen, 76000, Rouen, France.
AD  - CHU Rouen, CIC-CRB U1404, 76000, Rouen, France.
LA  - eng
SI  - ClinicalTrials.gov/NCT03681379
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230111
PL  - Switzerland
TA  - Clin Pharmacokinet
JT  - Clinical pharmacokinetics
JID - 7606849
RN  - 349552KRHK (Simendan)
RN  - 0 (N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide)
RN  - 0 (Anti-Bacterial Agents)
SB  - IM
EIN - Clin Pharmacokinet. 2023 Feb 8;:. PMID: 36752992
MH  - Infant, Newborn
MH  - Humans
MH  - Child
MH  - Simendan
MH  - *Extracorporeal Membrane Oxygenation
MH  - Prospective Studies
MH  - Critical Illness/therapy
MH  - Anti-Bacterial Agents/pharmacokinetics
EDAT- 2023/01/12 06:00
MHDA- 2023/03/14 06:00
CRDT- 2023/01/11 23:25
PHST- 2022/12/11 00:00 [accepted]
PHST- 2023/01/12 06:00 [pubmed]
PHST- 2023/03/14 06:00 [medline]
PHST- 2023/01/11 23:25 [entrez]
AID - 10.1007/s40262-022-01199-y [pii]
AID - 10.1007/s40262-022-01199-y [doi]
PST - ppublish
SO  - Clin Pharmacokinet. 2023 Feb;62(2):335-348. doi: 10.1007/s40262-022-01199-y. Epub 
      2023 Jan 11.