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Retrospective Evaluation of Milrinone Pharmacokinetics in Children With Kidney Injury
Katja M Gist1, Tomoyuki Mizuno, Stuart L Goldstein
1*The Heart Institute, Children's Hospital Colorado, Department of Pediatrics, University of Colorado, Aurora; ‡Center for Acute Care Nephrology, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine; and †Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH.
Objectives:
Milrinone is an inotropic agent with vasodilating properties used in the treatment of ventricular dysfunction. Milrinone is predominantly eliminated by the kidneys and accumulates in the setting of acute kidney injury (AKI). The purpose of this study was to evaluate milrinone pharmacokinetics in children with AKI with or without continuous renal replacement therapy (CRRT).
Methods:
Retrospective collection of milrinone therapeutic drug monitoring data in patients with AKI, including those requiring CRRT, through chart review from January 2008 to March 2014. Pharmacokinetic (PK) data were analyzed by Bayesian estimation using a pediatric population PK model (MW/Pharm). Clearance estimates were allometrically scaled to body weight.
Results:
Data on 11 patients were available for analysis. Three patients required CRRT. Milrinone concentrations during continuous infusion varied 30-fold and ranged from 44 to 1343 ng/mL. Of the 33 samples obtained in 11 patients, 24 were outside the target range (72.7%), with 16 (48.5%) above and 8 (24.2%) below. Patients with AKI had significantly lower milrinone clearance (4.72 ± 2.26 L/h per 70 kg) compared with published data in patients without AKI. There was large between-patient variability in milrinone clearance (range: 2.91-13.6 L/h per 70 kg). Clearance in patients on CRRT ranged from 2.8 to 7.19 L/h per 70 kg. A significant correlation between milrinone clearance and estimated creatinine clearance was observed (r = 0.70, P = 0.0097). Allometrically scaled milrinone clearance was lower in the youngest patients (younger than 2 years), suggestive of ongoing renal maturation and existing AKI.
Conclusions:
Pediatric patients with AKI have significantly lower milrinone clearance compared with published data in patients without AKI. Large variability was noted in milrinone concentrations, and they were frequently outside the target range. The large between-patient variability in milrinone concentrations suggests that dosing regimens should be individualized in this population of critically ill patients. Evaluation of PK model-based milrinone dose optimization and the use of biomarkers as predictors of changes in clearance warrant further study.
Insights
Pediatric patients with acute kidney injury (AKI) show significantly reduced milrinone clearance, leading to frequent out-of-range drug concentrations. Individualized dosing is crucial for critically ill children with AKI.
Area of Science:
- Pharmacology
- Nephrology
- Pediatric Critical Care
Background:
- Milrinone, an inotropic agent with vasodilating properties, is used for ventricular dysfunction.
- Kidney elimination makes milrinone prone to accumulation in acute kidney injury (AKI).
- Understanding milrinone pharmacokinetics in pediatric AKI is essential for safe and effective use.
Purpose of the Study:
- To evaluate milrinone pharmacokinetics in children experiencing acute kidney injury (AKI).
- To assess the impact of continuous renal replacement therapy (CRRT) on milrinone pharmacokinetics in pediatric AKI.
Main Methods:
- Retrospective analysis of therapeutic drug monitoring data for milrinone in pediatric patients with AKI (2008-2014).
- Bayesian estimation using a pediatric population pharmacokinetic (PK) model (MW/Pharm).
- Allometric scaling of clearance estimates to body weight.
Main Results:
- Significantly lower milrinone clearance in pediatric AKI patients (4.72 ± 2.26 L/h per 70 kg) compared to non-AKI populations.
- High variability in milrinone concentrations (72.7% outside target range), with frequent supra- and sub-therapeutic levels.
- Correlation between milrinone clearance and estimated creatinine clearance (r = 0.70, P = 0.0097); lower clearance noted in younger children (<2 years).
Conclusions:
- Pediatric AKI patients exhibit substantially reduced milrinone clearance and high concentration variability.
- Current dosing regimens may be inadequate, necessitating individualized treatment strategies.
- Further research into PK model-based dose optimization and predictive biomarkers is warranted.
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