Use of Monte Carlo simulation to prevent pharmacokinetics impairment of amiodarone under VV ECMO

ABSTRACT

Introduction: Acute Respiratory Distress Syndrome (ARDS) became a leading cause of ICU admission since the COVID-19 outbreak. Refractory ARDS can benefit from Veno-Venous Extra Corporeal Membrane Oxygenation (VV ECMO). Amiodarone is used for treating cardiac arrhythmias and shockable cardiac arrest during cardiopulmonary resuscitation (CPR). Data about amiodarone under VV ECMO are still lacking. In a previous work led on a model of ARDS in pigs ongoing CPR, we showed a pharmacokinetics impairment of amiodarone under VV ECMO. We aimed to establish a PK modelling of amiodarone concentrations. Material and methods: Nonlinear mixed effects modelling approach was used to analyse plasma concentrations. Impact of VV ECMO on amiodarone pharmacokinetic profile were investigated. Using our final model, different dosing schemes for amiodarone (10 000 Monte Carlo simulations) were simulated in animals on ECMO VV. Results: A two-compartment model with first-order absorption and elimination was able to accurately describe amiodarone plasma concentrations. Interindividual variability was retained for clearance and central volume of distribution. Amiodarone PK parameters were influenced by the ECMO covariable. All parameters were well estimated. Goodness of fit plots comforted the accuracy of the model. Predicted-corrected visual predictive check of the final model was satisfactory. Simulated amiodarone exposure showed that amiodarone 600 mg bolus is required under VV ECMO to achieve similar AUC observed in the control group. Discussion/Conclusion: In our model of ARDS in pigs with cardiac arrest and benefiting from CPR and VV ECMO, a two-compartment model with first-order absorption and elimination was able to accurately describe amiodarone plasma concentrations. VV ECMO significantly modified both central distribution volume and amiodarone clearance. From Monte-Carlo simulation, we showed that a 2-fold increase of amiodarone doses should be considered to reach efficient drug exposure under VV ECMO.