Milrinone therapeutic drug monitoring in a pediatric population: Development and validation of a quantitative liquid chromatography-tandem mass spectrometry method

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 < 83% across 3 levels of QC. Between-day precision was < 12%. The method was linear from 50 to 800 mu g/1; the lower limit of quantification was 22 mu g/l. Comparison with another LC-MS/MS method showed good agreement. Using this simplified method, turnaround times within 3-6 h 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. (C) 2017 Published by Elsevier B.V.