A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data
- 15 Downloads
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.
KeywordsAmiodarone Population pharmacokinetics Pediatrics Cardiac arrhythmias
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).
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.
- 1.Nadkarni VM, Larkin GL, Peberdy MA, Carey SM, Kaye W, Mancini ME, Nichol G, Lane-Truitt T, Potts J, Ornato JP, Berg RA, Registry National, of Cardiopulmonary Resuscitation Investigators (2006) First documented rhythm and clinical outcome from in-hospital cardiac arrest among children and adults. JAMA 295:50–57CrossRefPubMedGoogle Scholar
- 3.Kleinman ME, Chameides L, Schexnayder SM, Samson RA, Hazinski MF, Atkins DL, Berg MD, de Caen AR, Fink EL, Freid EB, Hickey RW, Marino BS, Nadkarni VM, Proctor LT, Qureshi FA, Sartorelli K, Topjian A, van der Jagt EW, Zaritsky AL (2010) Part 14: pediatric advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 122:S876–S908CrossRefPubMedGoogle Scholar
- 4.Silva JN, Erickson CC, Carter CD, Greene EA, Kantoch M, Collins KK, Miyake CY, Carboni MP, Rhee EK, Papez A, Anand V, Bowman TM, Van Hare GF, Participating Members of Pediatric and Congenital Electrophysiology Society (PACES) (2014) Management of pediatric tachyarrhythmias on mechanical support. Circ Arrhythm Electrophysiol 7:658–663CrossRefPubMedGoogle Scholar
- 36.Saul JP, Scott WA, Brown S, Marantz P, Acevedo V, Etheridge SP, Perry JC, Triedman JK, Burriss SW, Cargo P, Graepel J, Koskelo EK, Wang R, Intravenous Amiodarone Pediatric Investigators (2005) Intravenous amiodarone for incessant tachyarrhythmias in children: a randomized, double-blind, antiarrhythmic drug trial. Circulation 112:3470–3477CrossRefPubMedGoogle Scholar
- 38.Valdes SO, Donoghue AJ, Hoyme DB, Hammond R, Berg MD, Berg RA, Samson RA, American Heart Association Get With The Guidelines-Resuscitation Investigators (2014) Outcomes associated with amiodarone and lidocaine in the treatment of in-hospital pediatric cardiac arrest with pulseless ventricular tachycardia or ventricular fibrillation. Resuscitation 85:381–386CrossRefPubMedGoogle Scholar
- 39.Gonzalez D, Melloni C, Yogev R, Poindexter BB, Mendley SR, Delmore P, Sullivan JE, Autmizguine J, Lewandowski A, Harper B, Watt KM, Lewis KC, Capparelli EV, Benjamin DK Jr, Cohen-Wolkowiez M, Pharmaceuticals Best, for Children Act—Pediatric Trials Network Administrative Core Committee (2014) Use of opportunistic clinical data and a population pharmacokinetic model to support dosing of clindamycin for premature infants to adolescents. Clin Pharmacol Ther 96:429–437CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Dennis J, Schnabel RB (1996) Numerical methods for unconstrained optimization and nonlinear equations. Class Appl Math 10(1137/1):9781611971200Google Scholar