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

doi:10.1007/s10928-018-9576-y

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^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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 language	English (US)
Pages (from-to)	419-430
Number of pages	12
Journal	Journal of Pharmacokinetics and Pharmacodynamics
Volume	45
Issue number	3
DOIs	https://doi.org/10.1007/s10928-018-9576-y
State	Published - Jun 1 2018

Funding

Disclosures S.H.D. receives support from the National Institutes of Health (NIH)/National Institute of General Medicine Sciences (T32GM086330). C.P.H receives salary support for research from the National Center for Advancing Translational Sciences of the NIH (UL1TR001117). M.C.W. receives support for research from the NIH (1R01-HD076676-01A1), the National Institute of Allergy and Infectious Diseases (HHSN272201500006I and HHSN272201300017I), the National Institute of Child Health and Human Development (HHSN275201000003I), the Biomedical Advanced Research and Development Authority (HHSO100201300009C), and industry for drug development in adults and children (www.dcri.duke.edu/research/ coi.jsp). The other authors have no potential conflicts of interest. This work was funded under National Institute of Child Health and Human Development contract HHSN275201000003I for the Pediatric Trials Network (Principal Investigator Daniel K. Benjamin). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The assay measuring amiodarone concentrations was performed at OpAns Laboratory (Durham, NC). Gary Furda, Duke Clinical Research Institute, Durham, NC; Daniel K. Benjamin, Duke Clinical Research Institute, Durham, NC; Edmund Capparelli, UC San Diego, San Diego, CA; Gregory L. Kearns, Arkansas Children?s Hospital Research Institute, Little Rock, AR; Ian M. Paul, Penn State College of Medicine, Hershey, PA; Christoph P. Hornik, Duke Clinical Research Institute, Durham, NC; Kelly Wade, Children?s Hospital of Philadelphia, Philadelphia, PA. David Siegel and Perdita Taylor-Zapata Ravinder Anand and Gina Simone Duke Clinical Research Institute: Tammy Day (clinical research associate). Medical University of South Carolina Children?s Hospital: Hibah Al Nasiri (SC), Ann Frampton (SC), Patricia Infinger (SC). Ann and Robert H. Lurie Children?s Hospital of Chicago: Laura Fearn (SC). University of Louisville-KCPCRU and Norton Children?s Hospital: Tressa Bratton (SC), Jacqueline Perry (SC), Jennifer Comings (SC). Oregon Health and Science University: Kira Clark (SC). University of Maryland: Donna Cannonier (SC). University of North Carolina at Chapel Hill: Janice Bernhardt (SC). The Children?s Hospital Colorado: Peter Mourani (Site PI), Susan Gunn (SC). University of Virginia Children?s Hospital: Michelle Adu-Darko (Site PI), Robin Kelly (SC). Rainbow Babies and Children?s Hospital: Stuart Goldstein (Site PI), Tara Terrell (SC). Duke University Medical Center: Kevin Watt (Site PI), Samantha Wrenn (SC), Christie Milleson (SC). S.H.D. receives support from the National Institutes of Health (NIH)/National Institute of General Medicine Sciences (T32GM086330). C.P.H receives salary support for research from the National Center for Advancing Translational Sciences of the NIH (UL1TR001117). M.C.W. receives support for research from the NIH (1R01-HD076676-01A1), the National Institute of Allergy and Infectious Diseases (HHSN272201500006I and HHSN272201300017I), the National Institute of Child Health and Human Development (HHSN275201000003I), the Biomedical Advanced Research and Development Authority (HHSO100201300009C), and industry for drug development in adults and children (www.dcri.duke.edu/research/coi.jsp). The other authors have no potential conflicts of interest. Acknowledgements This work was funded under National Institute of Child Health and Human Development contract HHSN275201000003I for the Pediatric Trials Network (Principal Investigator Daniel K. Benjamin). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The assay measuring amiodarone concentrations was performed at OpAns Laboratory (Durham, NC).

Keywords

Amiodarone
Cardiac arrhythmias
Pediatrics
Population pharmacokinetics

ASJC Scopus subject areas

Pharmacology

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10.1007/s10928-018-9576-y

Cite this

Dallefeld, S. H., Atz, A. M., Yogev, R., Sullivan, J. E., Al-Uzri, A., Mendley, S. R., Laughon, M., Hornik, C. P., Melloni, C., Harper, B., Lewandowski, A., Mitchell, J., Wu, H., Green, T. P., & 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, 45(3), 419-430. https://doi.org/10.1007/s10928-018-9576-y

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

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

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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, vol. 45, no. 3, pp. 419-430. https://doi.org/10.1007/s10928-018-9576-y

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T1 - A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data

AU - Dallefeld, Samantha H.

AU - Atz, Andrew M.

AU - Yogev, Ram

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

AU - Wu, Huali

AU - Green, Thomas P.

AU - Cohen-Wolkowiez, Michael

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Y1 - 2018/6/1

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.

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

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