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A physiologically-based pharmacokinetic modeling approach for dosing amiodarone in children on ECMO
Venkata K Yellepeddi1,2, John Porter Hunt1, Danielle J Green1,3
1Division of Clinical Pharmacology, Department of Pediatrics, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, Utah, USA.
Insights
This study developed a pharmacokinetic model to determine amiodarone dosing for pediatric patients on extracorporeal membrane oxygenation (ECMO). Simulations suggest specific intravenous doses for neonates, infants, children, and adolescents on ECMO.
Area of Science:
- Pharmacology
- Pediatric Critical Care
- Computational Modeling
Background:
- Extracorporeal membrane oxygenation (ECMO) is vital for pediatric cardiac arrest.
- Amiodarone is recommended for ventricular arrhythmias but lacks pediatric ECMO dosing guidelines.
- Drug adsorption to ECMO components alters pharmacokinetics, necessitating specific dosing strategies.
Purpose of the Study:
- To develop a physiologically-based pharmacokinetic (PBPK) model for amiodarone in pediatric ECMO patients.
- To establish evidence-based amiodarone dosing recommendations for pediatric patients on ECMO.
- To demonstrate the utility of PBPK modeling for optimizing drug therapy in pediatric ECMO.
Main Methods:
- Developed a PBPK model of amiodarone, scaling from adults to children with age-specific CYP450 maturation.
- Incorporated an ECMO compartment parameterized with in vitro amiodarone adsorption data.
- Validated model predictions against observed amiodarone concentrations in pediatric ECMO patients.
Main Results:
- The PBPK model accurately predicted amiodarone concentrations in pediatric ECMO patients (average fold error 0.5-2).
- Simulations supported specific i.v. bolus doses: 22 mg/kg (neonates), 13 mg/kg (infants), 8 mg/kg (children), and 6 mg/kg (adolescents).
- The model successfully accounts for amiodarone adsorption to ECMO circuits.
Conclusions:
- Physiologically-based pharmacokinetic modeling provides a robust method for determining amiodarone dosage in pediatric ECMO.
- Recommended amiodarone doses vary by age group in pediatric patients requiring ECMO.
- This PBPK approach can guide dosing for other medications used in pediatric 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.
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