Population Pharmacokinetics of Milrinone in Infants, Children, and Adolescents

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.

Keywords: children; creatinine clearance; infants; milrinone; pharmacokinetics.

© 2019, The American College of Clinical Pharmacology.

Figures

Figure 1.

Final population pharmacokinetic model goodness-of-fit plots: observed concentrations vs. population predictions (A) and individual predictions (B), and conditional-weighted residuals against time after first dose (C) and population predictions (D). The solid black line represents the line of unity, the dashed line is a linear regression line [(A) and (B)] or a Loess smoother [(C) and (D)].

Figure 2.

Prediction corrected visual predictive check for the final population pharmacokinetic model. Seven percent of the observations are outside of the 90% prediction interval. The shaded area represents the 90% prediction interval, the dashed line the median predicted concentrations, and the solid line the median observed concentrations.

Figure 3.

Empirical Bayesian Estimates of milrinone half-life by estimated creatinine clearance (CrCl). Outer limits of the boxes are 25th and 75th percentiles, vertical lines inside the box the 50th percentile, while whiskers are 1.5 times the interquartile range. Outlier values are shown.

Figure 4.

Median simulated milrinone plasma concentration time curve in individual subjects with variable creatinine clearance following a 25 mcg/kg loading dose followed by a 0.25 mcg/kg/min continuous infusion in a 3 kg neonate (A); following a 50 mcg/kg loading followed by a 0.5 mcg/kg/min continuous infusion in a 3 kg neonate (B); following a 25 mcg/kg loading dose followed by a 0.25 mcg/kg/min continuous infusion in a 13 kg child (2 years of age) (C); following a 50 mcg/kg loading dose followed by a 0.5 mcg/kg/min continuous infusion in a 13 kg child (2 years of age) (D); following a 25 mcg/kg loading dose followed by a 0.25 mcg/kg/min continuous infusion in a 40 kg adolescent (12 years of age) (E); following a 50 mcg/kg loading followed by a 0.5 mcg/kg/min continuous infusion in a 40 kg adolescent (12 years of age) (F).

Figure 4.

Median simulated milrinone plasma concentration time curve in individual subjects with variable creatinine clearance following a 25 mcg/kg loading dose followed by a 0.25 mcg/kg/min continuous infusion in a 3 kg neonate (A); following a 50 mcg/kg loading followed by a 0.5 mcg/kg/min continuous infusion in a 3 kg neonate (B); following a 25 mcg/kg loading dose followed by a 0.25 mcg/kg/min continuous infusion in a 13 kg child (2 years of age) (C); following a 50 mcg/kg loading dose followed by a 0.5 mcg/kg/min continuous infusion in a 13 kg child (2 years of age) (D); following a 25 mcg/kg loading dose followed by a 0.25 mcg/kg/min continuous infusion in a 40 kg adolescent (12 years of age) (E); following a 50 mcg/kg loading followed by a 0.5 mcg/kg/min continuous infusion in a 40 kg adolescent (12 years of age) (F).

Figure 4.

Median simulated milrinone plasma concentration time curve in individual subjects with variable creatinine clearance following a 25 mcg/kg loading dose followed by a 0.25 mcg/kg/min continuous infusion in a 3 kg neonate (A); following a 50 mcg/kg loading followed by a 0.5 mcg/kg/min continuous infusion in a 3 kg neonate (B); following a 25 mcg/kg loading dose followed by a 0.25 mcg/kg/min continuous infusion in a 13 kg child (2 years of age) (C); following a 50 mcg/kg loading dose followed by a 0.5 mcg/kg/min continuous infusion in a 13 kg child (2 years of age) (D); following a 25 mcg/kg loading dose followed by a 0.25 mcg/kg/min continuous infusion in a 40 kg adolescent (12 years of age) (E); following a 50 mcg/kg loading followed by a 0.5 mcg/kg/min continuous infusion in a 40 kg adolescent (12 years of age) (F).

Figure 5.

Simulated steady-state milrinone plasma concentration (Css) by weight, age, and creatinine clearance following a 0.25 mcg/kg/min continuous infusion (A); and during a 0.5 mcg/kg/min continuous infusion (B). Dashed lines represent the upper and lower limit of the therapeutic range (100 ng/mL and 300 ng/mL, respectively). Outer limits of the boxes are 25th and 75th percentiles, vertical lines inside the box are the 50th percentile, while whiskers are 1.5 times the interquartile range. Outlier values are not shown.