Population Pharmacokinetics of Milrinone in Infants, Children, and Adolescents.

Published

Journal Article

Milrinone is a type 3 phosphodiesterase inhibitor used to improve cardiac output in critically ill infants and children. Milrinone is primarily excreted unchanged in the urine, raising concerns for toxic accumulation in the setting of renal dysfunction of critical illness. We developed a population pharmacokinetic model of milrinone using nonlinear mixed-effects modeling in NONMEM to perform dose-exposure simulations in children with variable renal function. We included children aged <21 years who received intravenous milrinone per clinical care. Plasma milrinone concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay (range 1-5000 ng/mL). We performed dose-exposure simulations targeting steady-state therapeutic concentrations of 100-300 ng/mL previously established in adults and children with cardiac dysfunction. We simulated concentrations over 48 hours in typical subjects with decreasing creatinine clearance (CrCl), estimated using the updated bedside Schwartz equation. Seventy-four patients contributed 111 plasma samples (concentration range, 4-634 ng/mL). The median (range) postmenstrual age (PMA) was 3.7 years (0-18), and median weight (WT) was 13.1 kg (2.6-157.7). The median serum creatinine and CrCl were 0.5 mg/dL (0.1-3.1) and 117.2 mL/min/1.73 m2 (13.1-261.3), respectively. A 1-compartment model characterized the pharmacokinetic data well. The final model parameterization was: Clearance (L/h) = 15.9*(WT [kg] / 70)0.75 * (PMA1.12 / (67.71.12 +PMA1.12 )*(CrCl / 117)0.522 ; and Volume of Distribution (L) = 32.2*(WT [kg] / 70). A loading dose of 50 µg/kg followed by a continuous infusion of 0.5 µg/kg/min resulted in therapeutic concentrations, except when CrCl was severely impaired at ≤30 mL/min/1.73 m2 . In this setting, a 25 µg/kg loading dose and 0.25 µg/kg/min continuous infusion resulted in therapeutic exposures.

Full Text

Duke Authors

Cited Authors

  • Hornik, CP; Yogev, R; Mourani, PM; Watt, KM; Sullivan, JE; Atz, AM; Speicher, D; Al-Uzri, A; Adu-Darko, M; Payne, EH; Gelber, CE; Lin, S; Harper, B; Melloni, C; Cohen-Wolkowiez, M; Gonzalez, D; Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee,

Published Date

  • December 2019

Published In

Volume / Issue

  • 59 / 12

Start / End Page

  • 1606 - 1619

PubMed ID

  • 31317556

Pubmed Central ID

  • 31317556

Electronic International Standard Serial Number (EISSN)

  • 1552-4604

Digital Object Identifier (DOI)

  • 10.1002/jcph.1499

Language

  • eng

Conference Location

  • England