Developmental Pharmacokinetics and Age-Appropriate Dosing Design of Milrinone in Neonates and Infants with Acute Kidney Injury Following Cardiac Surgery
Background and Objective
Milrinone is used for the prevention of low cardiac output syndrome in pediatric patients after cardiac surgery. Milrinone is mainly eliminated by the kidneys; however, there is limited information on milrinone pharmacokinetics in infants who have acute kidney injury (AKI). The aim of this study was to develop a milrinone population pharmacokinetic model in neonates and infants with or without AKI. The developed milrinone pharmacokinetic model was utilized for a Monte Carlo simulation analysis to identify age-appropriate dosing regimens in neonates and infants.
Population pharmacokinetic analysis was performed with a total of 1088 serum milrinone concentrations obtained from 92 infants as part of a prospective clinical study in neonates and infants following cardiac surgery (ClinicalTrials.gov identifier NCT01966237). AKI stages were determined based on the Kidney Injury Improving Global Outcomes (KDIGO) Clinical Practice Guideline within the first three postoperative days.
A two-compartment model was found to adequately describe the pharmacokinetic data. Allometrically scaled body weight, AKI stages, and maturation function were identified as significant predictors of milrinone clearance. The proposed dosing regimens for milrinone continuous infusions were determined based on a target concentration attainment of simulated steady-state concentration and covered three age groups across 0–12 months of age for each AKI stage.
This study provides a milrinone population pharmacokinetic model in neonates and infants and captures the developmental changes in clearance. Age-appropriate dosing regimens were determined based on the simulation analysis with the developed pharmacokinetic model. The findings will facilitate model-informed precision dosing of milrinone in infants with or without AKI.
We would like to thank Dr. Eileen King (Cincinnati Children’s Hospital Medical Center) for her scientific inputs.
Compliance with Ethical Standards
The original prospective study (ClinicalTrials.gov identifier NCT01966237) was funded by the Thrasher Pediatric Research Foundation and supported by the Center for Acute Care Nephrology, the Heart Institute Research Core, and the Division of Critical Care Medicine at Cincinnati Children’s Hospital Medical Center.
Conflict of interest
Tomoyuki Mizuno, Katja M. Gist, Zhiqian Gao, Michael F Wempe, Jeffrey Alten, David S. Cooper, Stuart L. Goldstein, and Alexander A. Vinks declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 22.Holford N. The visual predictive check - superiority to standard diagnostic (Rorschach) plots [abstract no. 738]. Annual meeting of the population approach group in Europe (PAGE); 16–17 Jun 2005; Pamplona.Google Scholar
- 23.National Health and Nutrition Examination Survey. Questionnaires, datasets, and related documentation. https://wwwn.cdc.gov/nchs/nhanes/Default.aspx. Accessed 10 Dec 2018.
- 40.Children’s Hospital Medical Center, Cincinnati. Milrinone pharmacokinetics and acute kidney injury (MIL-PK) [ClinicalTrials.gov identifier NCT01966237]. US National Institutes of Health, ClinicalTrials.gov. https://www.clinicaltrials.gov. Accessed 7 Dec 2018.