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Pharmacokinetics of intravenous sildenafil in children with palliated single ventricle heart defects: effect of elevated hepatic pressures

Published online by Cambridge University Press:  01 April 2015

Kevin D. Hill ,
Mario R. Sampson ,
Jennifer S. Li ,
Robert D. Tunks ,
Scott R. Schulman  and
Michael Cohen-Wolkowiez
Kevin D. Hill*
Affiliation:
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, United States of America The Duke Clinical Research Institute, Durham, North Carolina, United States of America
Mario R. Sampson
Affiliation:
The Duke Clinical Research Institute, Durham, North Carolina, United States of America University of North Carolina Eshelman School of Pharmacy, Chapel Hill, North Carolina, United States of America
Jennifer S. Li
Affiliation:
The Duke Clinical Research Institute, Durham, North Carolina, United States of America
Robert D. Tunks
Affiliation:
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, United States of America
Scott R. Schulman
Affiliation:
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, United States of America
Michael Cohen-Wolkowiez
Affiliation:
The Duke Clinical Research Institute, Durham, North Carolina, United States of America
*
Correspondence to: Dr K. D. Hill, MD, 7506 Hospital North, DUMC Box 3090, Durham, NC 27710, United States of America. Tel: +919.668.8305; Fax: +919.681.8927; E-mail: kevin.hill@duke.edu
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Abstract

Aims

Sildenafil is frequently prescribed to children with single ventricle heart defects. These children have unique hepatic physiology with elevated hepatic pressures, which may alter drug pharmacokinetics. We sought to determine the impact of hepatic pressure on sildenafil pharmacokinetics in children with single ventricle heart defects.

Methods

A population pharmacokinetic model was developed using data from 20 single ventricle children receiving single-dose intravenous sildenafil during cardiac catheterisation. Non-linear mixed effect modelling was used for model development, and covariate effects were evaluated based on estimated precision and clinical significance.

Results

The analysis included a median (range) of 4 (2–5) pharmacokinetic samples per child. The final structural model was a two-compartment model for sildenafil with a one-compartment model for des-methyl-sildenafil (active metabolite), with assumed 100% sildenafil to des-methyl-sildenafil conversion. Sildenafil clearance was unaffected by hepatic pressure (clearance=0.62 L/hour/kg); however, clearance of des-methyl-sildenafil (1.94×(hepatic pressure/9)−1.33 L/hour/kg) was predicted to decrease ~7-fold as hepatic pressure increased from 4 to 18 mmHg. Predicted drug exposure was increased by ~1.5-fold in subjects with hepatic pressures ⩾10 versus <10 mmHg (median area under the curve=533 versus 792 µg*h/L).

Discussion

Elevated hepatic pressure delays clearance of the sildenafil metabolite – des-methyl-sildenafil – and increases drug exposure. We speculate that this results from impaired biliary clearance. Hepatic pressure should be considered when prescribing sildenafil to children. These data demonstrate the importance of pharmacokinetic assessments in patients with unique cardiovascular physiology that may affect drug metabolism.

Keywords

Single ventriclesildenafilpharmacokineticshepatic dysfunction
Type
Original Articles
Information
Cardiology in the Young , Volume 26 , Supplement 2 , February 2016 , pp. 354 - 362
Copyright
© Cambridge University Press 2015 

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Footnotes

*

Equal contributors.

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