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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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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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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).

The PTN publications committee

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.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development

David Siegel and Perdita Taylor-Zapata

The EMMES Corporation (Data Coordinating Center)

Ravinder Anand and Gina Simone

Pediatric trials network amiodarone study team, principal investigators (PIs), and study coordinators (SCs)

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).

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.

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Authors and Affiliations

  1. Duke Clinical Research Institute, Duke University School of Medicine, 2400 Pratt St, Durham, NC, 27705, USA

    Samantha H. Dallefeld, Christoph P. Hornik, Chiara Melloni, Barrie Harper, Huali Wu & Michael Cohen-Wolkowiez

  2. Medical University of South Carolina Children’s Hospital, Charleston, SC, USA

    Andrew M. Atz

  3. Ann and Robert H. Lurie Children’s Hospital of Chicago/Northwestern University, Chicago, IL, USA

    Ram Yogev & Thomas P. Green

  4. University of Louisville-KCPCRU and Norton Children’s Hospital, Louisville, KY, USA

    Janice E. Sullivan

  5. Oregon Health and Science University, Portland, OR, USA

    Amira Al-Uzri

  6. The University of Maryland, College Park, MD, USA

    Susan R. Mendley

  7. University of North Carolina-Chapel Hill, Chapel Hill, NC, USA

    Matthew Laughon

  8. The EMMES Corporation, Rockville, MD, USA

    Andrew Lewandowski & Jeff Mitchell

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  1. Samantha H. Dallefeld
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Correspondence to Michael Cohen-Wolkowiez.

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Supplementary material 1 (DOCX 31 kb)

10928_2018_9576_MOESM2_ESM.pdf

Supplementary material Fig. 1 Standard goodness-of-fit plots of the final model depicting only the PTN dataset. (The same data are represented by Fig. 1 but are presented here because the PTN data points are largely obscured in that figure by the larger number of data points from the Ramusovic dataset.) Observed versus population (A) and individual (B) predictions for the amiodarone model. The line of identity is indicated by a solid line. Conditional weighted residuals (CWRES) versus time after dose (C) and population predictions (D) for the base amiodarone PK model (PDF 73 kb)

10928_2018_9576_MOESM3_ESM.pdf

Supplementary material Fig. 2 Observed serum amiodarone concentrations in each patient versus time (hours). In subjects with more than one concentration, the model-predicted concentration–time course is illustrated with a solid line for the duration of the drug administration (PDF 655 kb)

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Dallefeld, S.H., Atz, A.M., Yogev, R. et al. A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data. J Pharmacokinet Pharmacodyn 45, 419–430 (2018). https://doi.org/10.1007/s10928-018-9576-y

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