title: Milrinone therapeutic drug monitoring in a pediatric population: Development and validation of a quantitative liquid chromatography-tandem mass spectrometry method.
abstract: BACKGROUND
  Milrinone is a potent selective phosphodiesterase type III inhibitor which stimulates myocardial function and improves myocardial relaxation. Although therapeutic monitoring is crucial to maintain therapeutic outcome, little data is available. A proof-of-principle study has been initiated in our institution to evaluate the clinical impact of optimizing milrinone dosing through therapeutic drug monitoring (TDM) in children following cardiac surgery. We developed a robust LC-MS/MS method to quantify milrinone in serum from pediatric patients in real-time.
  
  
  METHODS
  A liquid-liquid extraction procedure was used to prepare samples for analysis prior to measurement by LC-MS/MS. Performance characteristics, such as linearity, limit of quantitation (LOQ) and precision, were assessed. Patient samples were acquired post-surgery and analyzed to determine the concentration-time profile of the drug as well as to track turn-around-times.
  
  
  RESULTS
  Within day precision was <8.3% across 3 levels of QC. Between-day precision was <12%. The method was linear from 50 to 800μg/l; the lower limit of quantification was 22μg/l. Comparison with another LC-MS/MS method showed good agreement. Using this simplified method, turnaround times within 3-6h were achievable, and patient drug profiles demonstrated that some milrinone levels were either sub-therapeutic or in the toxic range, highlighting the importance for milrinone TDM.
  
  
  CONCLUSIONS
  This simplified and quick method proved to be analytically robust and able to provide therapeutic monitoring of milrinone in real-time in patients post-cardiac surgery.
authors.affiliation: Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Canada.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Raizman
authors.affiliation: Department of Anesthesiology, Hospital for Sick Children, Canada.
authors.forename: Katherine
authors.initials: K
authors.lastname: Taylor
authors.affiliation: Department of Critical Care Medicine, Hospital for Sick Children, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Parshuram
authors.affiliation: Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Canada. Electronic address: david.colantonio@sickkids.ca.
authors.forename: David A
authors.initials: DA
authors.lastname: Colantonio
mesh_terms: D001774:Blood Chemical Analysis / Q000379:methods*; D002648:Child; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D016903:Drug Monitoring / Q000379:methods*; D006801:Humans; D059625:Liquid-Liquid Extraction; D020105:Milrinone / Q000097:blood* / Q000302:isolation & purification; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D020105:Milrinone
keywords: Mass spectrometry; Milrinone; Pediatrics; Therapeutic drug monitoring