Impaired Pharmacokinetics of Amiodarone under Veno-Venous Extracorporeal Membrane Oxygenation: From Bench to Bedside

Mickaël Lescroart (1, 2, 3) , Claire Pressiat (4, 5) , Benjamin Péquignot (1, 2, 3) , N’guyen Tran (3) , Jean-Louis Hébert (6, 7) , Nassib Alsagheer (8) , Nicolas Gambier (9, 8) , Bijan Ghaleh (10, 5) , Julien Scala-Bertola (9, 8) , Bruno Levy (1, 2)

1 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
2 DCAC - Défaillance Cardiovasculaire Aiguë et Chronique
3 Faculté de Médecine [Nancy]
4 CHU Henri Mondor [Créteil]
5 IMRB - Institut Mondor de Recherche Biomédicale
6 Institut de cardiologie [CHU Pitié-Salpêtrière]
7 SU - Sorbonne Université
8 Service de Pharmacologie Clinique et Toxicologie [CHRU Nancy]
9 IMoPA - Ingénierie Moléculaire et Physiopathologie Articulaire
10 ENVA - École nationale vétérinaire d'Alfort

Background: Adjusting drug therapy under veno-venous extracorporeal membrane oxygenation (VV ECMO) is challenging. Although impaired pharmacokinetics (PK) under VV ECMO have been reported for sedative drugs and antibiotics, data about amiodarone are lacking. We evaluated the pharmacokinetics of amiodarone under VV ECMO both in vitro and in vivo. Methods: In vitro: Amiodarone concentration decays were compared between closed-loop ECMO and control stirring containers over a 24 h period. In vivo: Potassium-induced cardiac arrest in 10 pigs with ARDS, assigned to either control or VV ECMO groups, was treated with 300 mg amiodarone injection under continuous cardiopulmonary resuscitation. Pharmacokinetic parameters Cmax, Tmax AUC and F were determined from both direct amiodarone plasma concentrations observation and non-linear mixed effects modeling estimation. Results: An in vitro study revealed a rapid and significant decrease in amiodarone concentrations in the closed-loop ECMO circuitry whereas it remained stable in control experiment. In vivo study revealed a 32% decrease in the AUC and a significant 42% drop of Cmax in the VV ECMO group as compared to controls. No difference in Tmax was observed. VV ECMO significantly modified both central distribution volume and amiodarone clearance. Monte Carlo simulations predicted that a 600 mg bolus of amiodarone under VV ECMO would achieve the amiodarone bioavailability observed in the control group. Conclusions: This is the first study to report decreased amiodarone bioavailability under VV ECMO. Higher doses of amiodarone should be considered for effective amiodarone exposure under VV ECMO.

Mots clés: Monte-Carlo simulations; VV ECMO; amiodarone; pharmacokinetics

Domaines: Pharmacologie

Mickaël Lescroart, Claire Pressiat, Benjamin Péquignot, N’guyen Tran, Jean-Louis Hébert, et al.. Impaired Pharmacokinetics of Amiodarone under Veno-Venous Extracorporeal Membrane Oxygenation: From Bench to Bedside. Pharmaceutics, 2022, 14 (5), pp.974. ⟨10.3390/pharmaceutics14050974⟩. ⟨hal-03763676⟩