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The relationship between simulated milrinone exposure and hypotension in children

Published online by Cambridge University Press:  05 August 2021

Sarah Jane Commander ,
Daniel Gonzalez ,
Karan R. Kumar ,
Tracy Spears ,
Michael Cohen-Wolkowiez ,
Kanecia O. Zimmerman ,
Stephen J. Balevic  and
Christoph P. Hornik Open the ORCID record for Christoph P. Hornik [Opens in a new window]
Sarah Jane Commander
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA Department of Surgery, Duke University Medical Center, Durham, NC, USA
Daniel Gonzalez
Affiliation:
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Karan R. Kumar
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
Tracy Spears
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA
Michael Cohen-Wolkowiez
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
Kanecia O. Zimmerman
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
Stephen J. Balevic
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
Christoph P. Hornik*
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
*
Author for correspondence: Christoph Hornik, MD, PhD, MPH, Department of Pediatrics, Duke University School of Medicine, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715 USA. Tel: 919-357-8145; Fax: 919-681-9457; E-mail: christoph.hornik@duke.edu
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Abstract

Introduction:

Hypotension is an adverse event that may be related to systemic exposure of milrinone; however, the true exposure–safety relationship is unknown.

Methods:

Using the Pediatric Trials Network multicentre repository, we identified children ≤17 years treated with milrinone. Hypotension was defined according to age, using the Pediatric Advanced Life Support guidelines. Clinically significant hypotension was defined as hypotension with concomitant lactate >3 mg/dl. A prior population pharmacokinetic model was used to simulate milrinone exposures to evaluate exposure–safety relationships.

Results:

We included 399 children with a median (quarter 1, quarter 3) age of 1 year (0,5) who received 428 intravenous doses of milrinone (median infusion rate 0.31 mcg/kg/min [0.29,0.5]). Median maximum plasma milrinone concentration was 110.7 ng/ml (48.4,206.2). Median lowest systolic and diastolic blood pressures were 74 mmHg (60,85) and 35 mmHg (25,42), respectively. At least 1 episode of hypotension occurred in 178 (45%) subjects; clinically significant hypotension occurred in 10 (2%). The maximum simulated milrinone plasma concentrations were higher in subjects with clinically significant hypotension (251 ng/ml [129,329]) versus with hypotension alone (86 ng/ml [44, 173]) versus without hypotension (122 ng/ml [57, 208], p = 0.002); however, this relationship was not retained on multivariable analysis (odds ratio 1.01; 95% confidence interval 0.998, 1.01).

Conclusions:

We successfully leveraged a population pharmacokinetic model and electronic health record data to evaluate the relationship between simulated plasma concentration of milrinone and systemic hypotension occurrence, respectively, supporting the broader applicability of our novel, efficient, and cost-effective study design for examining drug exposure–response and –safety relationships.

Keywords

Milrinonehypotensionpopulation pharmacokineticssimulated concentrationreal-world data
Type
Original Article
Information
Cardiology in the Young , Volume 32 , Issue 5 , May 2022 , pp. 782 - 788
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Copyright
© The Author(s), 2021. Published by Cambridge University Press

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