Retrospective Evaluation of Milrinone Pharmacokinetics in Children With Kidney Injury

Abstract

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.

Population Pharmacokinetics of Milrinone in Infants, Children, and Adolescents

“…Based on our final PopPK model, children with an estimated CrCl of 30 mL/min/1.73 m 2 , indicative of severe renal impairment as defined by the FDA, had a 65% lower milrinone CL than children with an estimated CrCl of 117 mL/min/1.73 m 2 (5.9 L/h/70 kg vs 15.9 L/h/70 kg), the median estimated value in our study cohort . This decrease in CL is comparable to findings from a prior study of 11 children aged 3 weeks to 20 years of age diagnosed with acute kidney injury with or without continuous renal replacement therapy requirement (estimated CrCl 2.5‐103 mL/min), where the mean milrinone CL was 4.7 L/h/70 kg . In this prior study, milrinone CL was estimated using PopPK modeling based on scavenged sampling, with only allometrically scaled weight tested as a covariate, and CL being the only population parameter estimated.…”

“…In a more recent 2‐compartment PopPK model developed in infants <12 months of age who received milrinone after cardiac surgery, milrinone CL was estimated at 7.91 L/h/70 kg . Importantly, milrinone CL has been previously shown to increase with age in both infant cohorts and in cohorts including children up to 6 years of age . In our covariate analysis, the effect of age on CL was best represented by an E max maturation model using PMA, and estimation of maturation function parameters rather than fixing to previously published values resulted in superior model fit.…”

“…Our Hill coefficient estimate similarly lacked precision, as illustrated by the wide range of values estimated during bootstrapping. Despite this lack of precision, we can speculate that maturational effects primarily responsible for milrinone CL likely include changes in renal function, in particular the ontogeny of renal transporters that may be responsible for active secretion, given that >80% of the parent drug is recovered unchanged in the urine and that mean renal CL in healthy adults (300 mL/min) is in excess of glomerular filtration . Because the primary transporters that may be responsible for active secretion of milrinone are unknown, characteristics of the maturational function of milrinone CL remain speculative.…”

“…We are also unable to definitively comment on exposures associated with adverse events, as safety data were not comprehensively collected in our study. While some of these limitations may be overcome in a prospective PK, pharmacodynamics/efficacy, and safety trial of milrinone, consideration should also be given to the use of therapeutic drug monitoring for the titration of milrinone in children with or at risk for renal impairments, as previously suggested by others …”

“…Population PK (PopPK) models have been developed in different pediatric populations with both weight and age as covariates relevant for characterizing CL. The effects of variable renal function on milrinone CL in children are complex, involving an interplay between maturation of organ function, underlying disease processes, therapeutic benefits of milrinone, and milrinone toxicity, all affecting renal CL . In a retrospective analysis of therapeutic drug monitoring data from a single center, a significant correlation between estimated CrCl and milrinone CL was observed, a PopPK model was developed, and the need for dose individualization was highlighted .…”