title: Evaluation and optimisation of current milrinone prescribing for the treatment and prevention of low cardiac output syndrome in paediatric patients after open heart surgery using a physiology-based pharmacokinetic drug-disease model.
abstract: OBJECTIVE
  Milrinone is the drug of choice for the treatment and prevention of low cardiac output syndrome (LCOS) in paediatric patients after open heart surgery across Europe. Discrepancies, however, among prescribing guidance, clinical studies and practice pattern require clarification to ensure safe and effective prescribing. However, the clearance prediction equations derived from classical pharmacokinetic modelling provide limited support as they have recently failed a clinical practice evaluation. Therefore, the objective of this study was to evaluate current milrinone dosing using physiology-based pharmacokinetic (PBPK) modelling and simulation to complement the existing pharmacokinetic knowledge and propose optimised dosing regimens as a basis for improving the standard of care for paediatric patients.
  
  
  METHODS
  A PBPK drug-disease model using a population approach was developed in three steps from healthy young adults to adult patients and paediatric patients with and without LCOS after open heart surgery. Pre- and postoperative organ function values from adult and paediatric patients were collected from literature and integrated into a disease model as factorial changes from the reference values in healthy adults aged 20-40 years. The disease model was combined with the PBPK drug model and evaluated against existing pharmacokinetic data. Model robustness was assessed by parametric sensitivity analysis. In the next step, virtual patient populations were created, each with 1,000 subjects reflecting the average adult and paediatric patient characteristics with regard to age, sex, bodyweight and height. They were integrated into the PBPK drug-disease model to evaluate the effectiveness of current milrinone dosing in achieving the therapeutic target range of 100-300 ng/mL milrinone in plasma. Optimised dosing regimens were subsequently developed.
  
  
  RESULTS
  The pharmacokinetics of milrinone in healthy young adults as well as adult and paediatric patients were accurately described with an average fold error of 1.1 ± 0.1 (mean ± standard deviation) and mean relative deviation of 1.5 ± 0.3 as measures of bias and precision, respectively. Normalised maximum sensitivity coefficients for model input parameters ranged from -0.84 to 0.71, which indicated model robustness. The evaluation of milrinone dosing across different paediatric age groups showed a non-linear age dependence of total plasma clearance and exposure differences of a factor 1.4 between patients with and without LCOS for a fixed dosing regimen. None of the currently used dosing regimens for milrinone achieved the therapeutic target range across all paediatric age groups and adult patients, so optimised dosing regimens were developed that considered the age-dependent and pathophysiological differences.
  
  
  CONCLUSIONS
  The PBPK drug-disease model for milrinone in paediatric patients with and without LCOS after open heart surgery highlights that age, disease and surgery differently impact the pharmacokinetics of milrinone, and that current milrinone dosing for LCOS is suboptimal to maintain the therapeutic target range across the entire paediatric age range. Thus, optimised dosing strategies are proposed to ensure safe and effective prescribing.
authors.affiliation: Department of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-Universität Düsseldorf, Building 26.22.02, Room 21, Universitätsstrasse 1, 40225, Düsseldorf, Germany, winnie.vogt@gmail.com.
authors.forename: Winnie
authors.initials: W
authors.lastname: Vogt
mesh_terms: D000293:Adolescent; D000328:Adult; D002303:Cardiac Output, Low / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D006348:Cardiac Surgical Procedures; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D020105:Milrinone / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008954:Models, Biological; D055815:Young Adult
chemical_list: D002316:Cardiotonic Agents; D020105:Milrinone