A physiologically-based pharmacokinetic modeling approach for dosing amiodarone in children on ECMO

Abstract

Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass device commonly used to treat cardiac arrest in children. The American Heart Association guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care recommend using amiodarone as a first-line agent to treat ventricular arrhythmias in children with cardiac arrest. However, there are no dosing recommendations for amiodarone to treat ventricular arrhythmias in pediatric patients on ECMO. Amiodarone has a high propensity for adsorption to the ECMO components due to its physicochemical properties leading to altered pharmacokinetics (PK) in ECMO patients. The change in amiodarone PK due to interaction with ECMO components may result in a difference in optimal dosing in patients on ECMO when compared with non-ECMO patients. To address this clinical knowledge gap, a physiologically-based pharmacokinetic model of amiodarone was developed in adults and scaled to children, followed by the addition of an ECMO compartment. The pediatric model included ontogeny functions of cytochrome P450 (CYP450) enzyme maturation across various age groups. The ECMO compartment was parameterized using the adsorption data of amiodarone obtained from ex vivo studies. Model predictions captured observed concentrations of amiodarone in pediatric patients with ECMO well with an average fold error between 0.5 and 2. Model simulations support an amiodarone intravenous (i.v) bolus dose of 22 mg/kg (neonates), 13 mg/kg (infants), 8 mg/kg (children), and 6 mg/kg (adolescents). This PBPK modeling approach can be applied to explore the dosing of other drugs used in children on ECMO.

FIGURE 1

Adult optimized model. The physiologically‐based pharmacokinetic model concentration‐time predictions of amiodarone after intravenous injection doses of 150 mg (left panel) and 5 mg/kg (right panel). Solid black line represents the median predicted concentration; gray shaded area represents the 90% prediction interval; observed data from the adult development datasets, are represented by solid circles.

FIGURE 2

Adult verification model. The physiologically‐based pharmacokinetic model concentration‐time predictions of amiodarone after oral doses of 600 mg (top and middle panels) and 400 mg (bottom panel). Solid black line represents the median predicted concentrations; gray shaded area represents the 90% prediction interval; observed data from the adult verification datasets, , are represented by solid circles.

FIGURE 3

Pediatric extracorporeal membrane oxygenation (ECMO) physiologically‐based pharmacokinetic model (PBPK) predictions and observed data from pediatric ECMO patients. (a). PBPK model simulation without ECMO compartment, (b). PBPK model simulation with ECMO compartment added. The representative pediatric patient received a 125.51 mg/kg dose of amiodarone as intravenous infusion for a duration of 144.27 h. Solid black line is median predicted concentration; observed data are represented by dark circles.

FIGURE 4

The extracorporeal membrane oxygenation (ECMO) physiologically‐based pharmacokinetic model (PBPK)‐predicted optimized amiodarone dosing and exposure in children on ECMO across the pediatric age spectrum. Solid line represents the median, box represents interquartile range, and whiskers represent 90% prediction interval. The solid circles represent the outliers in the data. Dosing achieved the median target area under the concentration‐time curve (AUC)_0–24 (blue dashed line) in simulated children on ECMO in the first 24 h of therapy. In each individual box plot, the boxplots refer to the following from left to right: AHA recommended dose of 5 mg/kg in pediatric patients without ECMO, AHA recommended dose of 5 mg/kg in pediatric patients with ECMO, and optimized dosing in the same population. (a) Neonates (0 days to 1 month). (b) Infants (1 month to 1 year). (c) Children (1 year to 12 years). (d) Adolescents (13 to 17 years).