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

Kevin D. Hill, Mario R. Sampson, Jennifer S. Li, Robert D. Tunks, Scott R. Schulman, Michael Cohen-Wolkowiez

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 'copy'10 versus <10 mmHg (median area under the curve=533 versus 792 g∗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.

Original languageEnglish (US)
Pages (from-to)354-362
Number of pages9
JournalCardiology in the Young
Volume26
Issue number2
DOIs
StatePublished - Feb 9 2015

Fingerprint

Heart Ventricles
Pharmacokinetics
Pressure
Liver
Pharmaceutical Preparations
Sildenafil Citrate
Cardiovascular Physiological Phenomena
Structural Models
Cardiac Catheterization
Area Under Curve

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health
  • Cardiology and Cardiovascular Medicine

Cite this

Hill, Kevin D. ; Sampson, Mario R. ; Li, Jennifer S. ; Tunks, Robert D. ; Schulman, Scott R. ; Cohen-Wolkowiez, Michael. / Pharmacokinetics of intravenous sildenafil in children with palliated single ventricle heart defects : Effect of elevated hepatic pressures. In: Cardiology in the Young. 2015 ; Vol. 26, No. 2. pp. 354-362.
@article{71aa2f72baf54902abe19a624a6faaf5,
title = "Pharmacokinetics of intravenous sildenafil in children with palliated single ventricle heart defects: Effect of elevated hepatic pressures",
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 'copy'10 versus <10 mmHg (median area under the curve=533 versus 792 g∗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.",
author = "Hill, {Kevin D.} and Sampson, {Mario R.} and Li, {Jennifer S.} and Tunks, {Robert D.} and Schulman, {Scott R.} and Michael Cohen-Wolkowiez",
year = "2015",
month = "2",
day = "9",
doi = "10.1017/S1047951115000359",
language = "English (US)",
volume = "26",
pages = "354--362",
journal = "Cardiology in the Young",
issn = "1047-9511",
publisher = "Cambridge University Press",
number = "2",

}

Pharmacokinetics of intravenous sildenafil in children with palliated single ventricle heart defects : Effect of elevated hepatic pressures. / Hill, Kevin D.; Sampson, Mario R.; Li, Jennifer S.; Tunks, Robert D.; Schulman, Scott R.; Cohen-Wolkowiez, Michael.

In: Cardiology in the Young, Vol. 26, No. 2, 09.02.2015, p. 354-362.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pharmacokinetics of intravenous sildenafil in children with palliated single ventricle heart defects

T2 - Effect of elevated hepatic pressures

AU - Hill, Kevin D.

AU - Sampson, Mario R.

AU - Li, Jennifer S.

AU - Tunks, Robert D.

AU - Schulman, Scott R.

AU - Cohen-Wolkowiez, Michael

PY - 2015/2/9

Y1 - 2015/2/9

N2 - 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 'copy'10 versus <10 mmHg (median area under the curve=533 versus 792 g∗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.

AB - 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 'copy'10 versus <10 mmHg (median area under the curve=533 versus 792 g∗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.

UR - http://www.scopus.com/inward/record.url?scp=84951189752&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84951189752&partnerID=8YFLogxK

U2 - 10.1017/S1047951115000359

DO - 10.1017/S1047951115000359

M3 - Article

C2 - 26197839

AN - SCOPUS:84951189752

VL - 26

SP - 354

EP - 362

JO - Cardiology in the Young

JF - Cardiology in the Young

SN - 1047-9511

IS - 2

ER -