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.

A systematic review of clinical study evidence for pulmonary vasodilator therapy following surgery with cardiopulmonary bypass in children with CHD

“…90 Indeed, recent analysis of milrinone highlighted the need for dose reduction in children with renal insufficiency. 69 Children with CHD undergoing surgery with cardiopulmonary bypass, especially those with underlying pulmonary hypertension, remain at high risk for post-operative morbidity and mortality, and further studies leveraging standardised endpoints and novel trial design are required to allow for evidence-based therapies and improved outcomes. Supplementary material.…”

“…15 Additionally, milrinone has a relatively long half-life compared to other inotropes and is primarily renally cleared, so both optimal dosing and timing of therapy in critically ill children at risk for acute kidney injury are important to define. 68,69 Two studies of milrinone met our inclusion criteria. Milrinone has demonstrated it can reduce post-operative low cardiac output syndrome in a multicenter, randomised, double-blind placebo control trial and is routinely used post-operatively to augment cardiac output.…”

The relationship between simulated milrinone exposure and hypotension in children

“…A previously developed population pharmacokinetic model for milrinone in children under 21 years of age 9 was used to simulate exposures in the subjects extracted from the electronic health record. The prior study was a multi-centre study that included 74 patients with 111 opportunistically collected plasma samples.…”

“…[6][7][8] Studies characterising the pharmacokinetics of milrinone have been performed in neonates and children; however, these studies were not intended, nor large enough, to detect dosing and exposure relationships to rare adverse events. 1,5,[9][10][11][12][13][14][15][16] Hypotension is a rare adverse event that may be related to systemic exposure of milrinone, but the true exposure-safety relationship in children is unknown. This knowledge gap is primarily due to difficulties measuring systemic exposures and the need for sufficiently large patient cohorts to detect these rare adverse events.…”

“…17 In this study, we leverage the available dosing and clinical data from a multicentre electronic health record-derived repository and a paediatric population pharmacokinetic model developed from opportunistically collected pharmacokinetic data to predict exposures in children treated with milrinone. 9 We then use these predicted exposures to characterise their relationship with safety data and systemic hypotension, which were collected in the electronic health record.…”