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A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published
Samantha H Dallefeld1, Andrew M Atz2, Ram Yogev3
1Duke Clinical Research Institute, Duke University School of Medicine, 2400 Pratt St, Durham, NC, 27705, USA.
Insights
This study developed a population pharmacokinetic model for amiodarone in infants under two years old. The model provides key pharmacokinetic parameters to guide amiodarone dosing in pediatric patients.
Area of Science:
- Pediatric Pharmacology
- Pharmacometrics
- Drug Metabolism and Pharmacokinetics
Background:
- Amiodarone is a critical antiarrhythmic for pediatric ventricular arrhythmias.
- Limited pharmacokinetic data exists for amiodarone in pediatric populations, especially infants.
- Understanding amiodarone pharmacokinetics is crucial for optimizing treatment in children.
Purpose of the Study:
- To develop a population pharmacokinetic (PopPK) model for amiodarone in infants.
- To characterize amiodarone's pharmacokinetic parameters in children under two years old.
- To provide a basis for improved amiodarone dosing regimens in pediatric patients.
Main Methods:
- A population pharmacokinetic model was developed using combined data from a pediatric study and literature.
- Data included 266 plasma drug concentrations from 45 infants (< 2 years old).
- A 3-compartment model was utilized, with body weight as a covariate, and validated using predictive checks and bootstrap analysis.
Main Results:
- The final PopPK model incorporated body weight as a covariate on volumes and clearances.
- Key estimated parameters included clearance (CL) of 0.25 L/kg/h, volume of distribution (Vd) of 93 L/kg, and terminal half-life of 266 hours.
- Model validation confirmed its predictive performance.
Conclusions:
- The developed amiodarone PopPK model offers valuable insights into its disposition in infants.
- This model can inform future studies aimed at optimizing amiodarone dosage regimens for pediatric use.
- Further research is warranted to refine amiodarone dosing strategies in neonates and children.
Abstract:
Amiodarone is a first-line antiarrhythmic for life-threatening ventricular fibrillation or ventricular tachycardia in children, yet little is known about its pharmacokinetics (PK) in this population. We developed a population PK (PopPK) model using samples collected via an opportunistic study design of children receiving amiodarone per standard of care supplemented by amiodarone PK data from the literature. Both study data and literature data were predominantly from infants < 2 years old, so our analysis was restricted to this group. The final combined dataset consisted of 266 plasma drug concentrations in 45 subjects with a median (interquartile range) postnatal age of 40.1 (11.0-120.4) days and weight of 3.9 (3.1-5.1) kg. Since the median sampling time after the first dose was short (study: 95 h; literature: 72 h) relative to the terminal half-life estimated in adult PopPK studies, values of the deep compartment volume and flow were fixed to literature values. A 3-compartment model best described the data and was validated by visual predictive checks and non-parametric bootstrap analysis. The final model included body weight as a covariate on all volumes and on both inter-compartmental and elimination clearances. The empiric Bayesian estimates for clearance (CL), volume of distribution at steady state, and terminal half-life were 0.25 (90% CL 0.14-0.36) L/kg/h, 93 (68-174) L/kg, and 266 (197-477) h, respectively. These studies will provide useful information for future PopPK studies of amiodarone in infants and children that could improve dosage regimens.
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