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

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          Abstract

          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.

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          Author and article information

          Journal
          J Clin Pharmacol
          Journal of clinical pharmacology
          Wiley
          1552-4604
          0091-2700
          Dec 2019
          : 59
          : 12
          Affiliations
          [1 ] Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
          [2 ] Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
          [3 ] The Children's Hospital Colorado, Aurora, CO, USA.
          [4 ] University of Louisville Norton Children's Hospital, Louisville, KY, USA.
          [5 ] Medical University of South Carolina Children's Hospital, Charleston, SC, USA.
          [6 ] Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
          [7 ] Oregon Health and Science University, Portland, OR, USA.
          [8 ] University of Virginia Children's Hospital, Charlottesville, VA, USA.
          [9 ] The EMMES Corporation, Rockville, MD, USA.
          [10 ] Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
          Article
          NIHMS1040948
          10.1002/jcph.1499
          6813877
          31317556
          61447aba-e90d-437a-89ec-870dec297bd1
          History

          pharmacokinetics,children,creatinine clearance,infants,milrinone

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