A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data

Samantha H. Dallefeld, Andrew M. Atz, Ram Yogev, Janice E. Sullivan, Amira Al-Uzri, Susan R. Mendley, Matthew Laughon, Christoph P. Hornik, Chiara Melloni, Barrie Harper, Andrew Lewandowski, Jeff Mitchell, Huali Wu, Thomas P. Green, Michael Cohen-Wolkowiez

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalJournal of Pharmacokinetics and Pharmacodynamics
DOIs
StateAccepted/In press - Feb 12 2018

Fingerprint

Amiodarone
Pharmacokinetics
Population
Half-Life
Ventricular Fibrillation
Standard of Care
Ventricular Tachycardia
Body Weight
Weights and Measures
Pharmaceutical Preparations

Keywords

  • Amiodarone
  • Cardiac arrhythmias
  • Pediatrics
  • Population pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology

Cite this

A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data. / Dallefeld, Samantha H.; Atz, Andrew M.; Yogev, Ram; Sullivan, Janice E.; Al-Uzri, Amira; Mendley, Susan R.; Laughon, Matthew; Hornik, Christoph P.; Melloni, Chiara; Harper, Barrie; Lewandowski, Andrew; Mitchell, Jeff; Wu, Huali; Green, Thomas P.; Cohen-Wolkowiez, Michael.

In: Journal of Pharmacokinetics and Pharmacodynamics, 12.02.2018, p. 1-12.

Research output: Contribution to journalArticle

Dallefeld, SH, Atz, AM, Yogev, R, Sullivan, JE, Al-Uzri, A, Mendley, SR, Laughon, M, Hornik, CP, Melloni, C, Harper, B, Lewandowski, A, Mitchell, J, Wu, H, Green, TP & Cohen-Wolkowiez, M 2018, 'A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data', Journal of Pharmacokinetics and Pharmacodynamics, pp. 1-12. https://doi.org/10.1007/s10928-018-9576-y
Dallefeld, Samantha H. ; Atz, Andrew M. ; Yogev, Ram ; Sullivan, Janice E. ; Al-Uzri, Amira ; Mendley, Susan R. ; Laughon, Matthew ; Hornik, Christoph P. ; Melloni, Chiara ; Harper, Barrie ; Lewandowski, Andrew ; Mitchell, Jeff ; Wu, Huali ; Green, Thomas P. ; Cohen-Wolkowiez, Michael. / A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data. In: Journal of Pharmacokinetics and Pharmacodynamics. 2018 ; pp. 1-12.
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AU - Sullivan, Janice E.

AU - Al-Uzri, Amira

AU - Mendley, Susan R.

AU - Laughon, Matthew

AU - Hornik, Christoph P.

AU - Melloni, Chiara

AU - Harper, Barrie

AU - Lewandowski, Andrew

AU - Mitchell, Jeff

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AU - Green, Thomas P.

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N2 - 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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