Population pharmacokinetics of milrinone in premature neonates to adolescents

Introduction: Milrinone is an inotrope and vasodilator used for prophylaxis or treatment of low cardiac output syndrome after weaning from cardiopulmonary bypass (CPB). It is renally eliminated and has an acceptable range of 100 – 300 μg/L, but weight-based dosing alone is associated with poor target attainment [1].
Aims: To develop a population PK model for milrinone from premature neonates to adolescents and to evaluate how age and renal function may predict dose individualisation.
Methods: Fifty patients (aged 4 days – 16 years) from Starship Children’s Hospital, Auckland, New Zealand, were studied after cardiac surgery supported by CPB. Data from another published study in premature neonates treated for prophylaxis of low systemic blood flow was available for a pooled PK analysis [2]. Population parameters were estimated using non-linear mixed effects modelling (NONMEM 7.5.1).
Results: A total of 369 milrinone measurements were available for analysis. A one compartment model with zero-order input and first-order elimination was used to describe milrinone disposition. Population parameters were CL 10.8 L/h/70 kg [95% CI 9.60, 11.9] and V 20.4 L/70 kg [95% CI 18.8, 22.5]. Covariates included size, postmenstrual age and renal function for CL, and size and postnatal age for V. Milrinone CL increased by 66.0%, [95% CI 47.9, 107] over time after bypass, with a half-time of 10.6 h, 95% CI [9.7, 16.3]. Milrinone V was 2.1 [95% CI 1.94, 2.24] times greater at birth than the population standard and decreased over the first days of life with a half-time of 0.955 days [95% CI 0.783, 1.05]. 
Discussion: Milrinone is predominately renally eliminated and so renal function is an important covariate describing variability in CL. Increasing CL over time likely reflects increasing cardiac output and renal perfusion due to milrinone and return to homeostasis following CPB. A loading dose of 50 μg/kg with age and renal function based dosing are recommended to improve target attainment.

[1] Vogt, Winnie. “Evaluation and optimisation of current milrinone prescribing for the treatment and prevention of low cardiac output syndrome in paediatric patients after open heart surgery using a physiology-based pharmacokinetic drug–disease model.” Clinical pharmacokinetics 53.1 (2014): 51-72.

[2] Paradisis, Mary, et al. “Population pharmacokinetics and dosing regimen design of milrinone in preterm infants.” Archives of Disease in Childhood-Fetal and Neonatal Edition 92.3 (2007): F204-F209.