Christoph P Hornik1, Nikolas J Onufrak2, P Brian Smith1, Michael Cohen-Wolkowiez1, Matthew M Laughon3, Reese H Clark4, Daniel Gonzalez2. 1. 1Department of Pediatrics,Duke Clinical Research Institute,Duke University,Durham,North Carolina,United States of America. 2. 2Eshelman School of Pharmacy,Division of Pharmacotherapy and Experimental Therapeutics,The University of North Carolina at Chapel Hill,Chapel Hill,North Carolina,United States of America. 3. 3Department of Pediatrics,Division of Neonatology,The University of North Carolina at Chapel Hill,Chapel Hill,North Carolina,United States of America. 4. 4Pediatrix-Obstetrix Center for Research and Education,Sunrise,Florida,United States of America.
Abstract
BACKGROUND: The relationship between sildenafil dosing, exposure, and systemic hypotension in infants is incompletely understood. OBJECTIVES: The aim of this study was to characterise the relationship between predicted sildenafil exposure and hypotension in hospitalised infants. METHODS: We extracted information on sildenafil dosing and clinical characteristics from electronic health records of 348 neonatal ICUs from 1997 to 2013, and we predicted drug exposure using a population pharmacokinetic model. RESULTS: We identified 232 infants receiving sildenafil at a median dose of 3.2 mg/kg/day (2.0, 6.0). The median steady-state area under the concentration-time curve over 24 hours (AUC24,SS) and maximum concentration of sildenafil (Cmax,SS,SIL) were 712 ng×hour/ml (401, 1561) and 129 ng/ml (69, 293), respectively. Systemic hypotension occurred in 9% of the cohort. In multivariable analysis, neither dosing nor exposure were associated with systemic hypotension: odds ratio=0.96 (95% confidence interval: 0.81, 1.14) for sildenafil dose; 0.87 (0.59, 1.28) for AUC24,SS; 1.19 (0.78, 1.82) for Cmax,SS,SIL. CONCLUSIONS: We found no association between sildenafil dosing or exposure with systemic hypotension. Continued assessment of sildenafil's safety profile in infants is warranted.
BACKGROUND: The relationship between sildenafil dosing, exposure, and systemic hypotension in infants is incompletely understood. OBJECTIVES: The aim of this study was to characterise the relationship between predicted sildenafil exposure and hypotension in hospitalised infants. METHODS: We extracted information on sildenafil dosing and clinical characteristics from electronic health records of 348 neonatal ICUs from 1997 to 2013, and we predicted drug exposure using a population pharmacokinetic model. RESULTS: We identified 232 infants receiving sildenafil at a median dose of 3.2 mg/kg/day (2.0, 6.0). The median steady-state area under the concentration-time curve over 24 hours (AUC24,SS) and maximum concentration of sildenafil (Cmax,SS,SIL) were 712 ng×hour/ml (401, 1561) and 129 ng/ml (69, 293), respectively. Systemic hypotension occurred in 9% of the cohort. In multivariable analysis, neither dosing nor exposure were associated with systemic hypotension: odds ratio=0.96 (95% confidence interval: 0.81, 1.14) for sildenafil dose; 0.87 (0.59, 1.28) for AUC24,SS; 1.19 (0.78, 1.82) for Cmax,SS,SIL. CONCLUSIONS: We found no association between sildenafil dosing or exposure with systemic hypotension. Continued assessment of sildenafil's safety profile in infants is warranted.
Authors: Nazzareno Galiè; Hossein A Ghofrani; Adam Torbicki; Robyn J Barst; Lewis J Rubin; David Badesch; Thomas Fleming; Tamiza Parpia; Gary Burgess; Angelo Branzi; Friedrich Grimminger; Marcin Kurzyna; Gérald Simonneau Journal: N Engl J Med Date: 2005-11-17 Impact factor: 91.245
Authors: Robyn J Barst; Maurice Beghetti; Tomas Pulido; Gary Layton; Irina Konourina; Min Zhang; D Dunbar Ivy Journal: Circulation Date: 2014-03-17 Impact factor: 29.690
Authors: A Vassalos; E Peng; D Young; S Walker; J Pollock; K Macarthur; F Lyall; M H D Danton Journal: Anaesthesia Date: 2011-04-04 Impact factor: 6.955
Authors: Kathryn N Farrow; Beezly S Groh; Paul T Schumacker; Satyan Lakshminrusimha; Lyubov Czech; Sylvia F Gugino; James A Russell; Robin H Steinhorn Journal: Circ Res Date: 2007-11-08 Impact factor: 17.367
Authors: Robin H Steinhorn; John P Kinsella; Christine Pierce; Ghazwan Butrous; Maria Dilleen; Michael Oakes; David L Wessel Journal: J Pediatr Date: 2009-12 Impact factor: 4.406
Authors: N Thakkar; D Gonzalez; M Cohen-Wolkowiez; M M Massaro; J Bernhardt; N R Zane; M M Laughon Journal: J Perinatol Date: 2016-05-12 Impact factor: 3.225
Authors: Christoph P Hornik; Andrew M Atz; Catherine Bendel; Francis Chan; Kevin Downes; Robert Grundmeier; Ben Fogel; Debbie Gipson; Matthew Laughon; Michael Miller; Michael Smith; Chad Livingston; Cindy Kluchar; Anne Heath; Chanda Jarrett; Brian McKerlie; Hetalkumar Patel; Christina Hunter Journal: Appl Clin Inform Date: 2019-05-08 Impact factor: 2.342