The relationship between simulated milrinone exposure and hypotension in children.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Commander, SJ; Gonzalez, D; Kumar, KR; Spears, T; Cohen-Wolkowiez, M; Zimmerman, KO; Balevic, SJ; Hornik, CP

Published Date

  • May 2022

Published In

Volume / Issue

  • 32 / 5

Start / End Page

  • 782 - 788

PubMed ID

  • 34350821

Pubmed Central ID

  • PMC8816969

Electronic International Standard Serial Number (EISSN)

  • 1467-1107

Digital Object Identifier (DOI)

  • 10.1017/S1047951121003103

Language

  • eng

Conference Location

  • England