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Objective Determine sildenafil exposure and hemodynamic effect in children after Fontan single-ventricle surgery. Design Prospective, dose-escalation trial. Setting Single-center, pediatric catheterization laboratory. Patients 9 children post Fontan single-ventricle surgical palliation and undergoing elective cardiac catheterization: Median (range) age and weight: 5.2 years (2.5–9.4) and 16.3 kg (9.5–28.1). Five children (55%) were male, and 6/9 (67%) had a systemic right ventricle. Interventions Catheterization and echocardiography performed before and immediately after single-dose intravenous sildenafil (0.25, 0.35, or 0.45 mg/kg over 20 minutes). Measurements Peak sildenafil and des-methyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography. Main Results Maximum sildenafil concentrations ranged from 124–646 ng/ml and were above the in vitro threshold needed for 77% phosphodiesterase type-5 (PDE-5) inhibition in 8/9 children and 90% inhibition in 7/7 of children with doses ≥0.35 mg/kg. Sildenafil improved stroke volume (+22%, p=0.05) and cardiac output (+10%, p=0.01) with no significant change in heart rate in 8/9 children. Sildenafil also lowered systemic (-16%, p=0.01) and pulmonary vascular resistance index (PVRI) in all 9 children (median baseline PVRI 2.4 [range: 1.3, 3.7]; decreased to 1.9 [0.8, 2.7] WU x m2; p=0.01) with no dose-response effect. Pulmonary arterial pressures decreased (−10%, p=0.02) and pulmonary blood flow increased (9%, p=0.02). There was no change in myocardial performance index and no adverse events. Conclusions After Fontan surgery, sildenafil infusion acutely improves cardiopulmonary hemodynamics, increasing cardiac index. For the range of doses studied, exposure was within the acute safety range reported in adult subjects.

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 catheterization. Nonlinear mixed effect modeling 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/H/kg); however, clearance of des-methyl-sildenafil (1.94 × (hepatic pressure/9)−1.33 L/h/kg) was predicted to decrease ~7 fold as hepatic pressure increased from 4 to 18 mm Hg. Predicted drug exposure was increased by ~1.5 fold in subjects with hepatic pressures ≥ 10 mm Hg versus < 10 mm Hg (median area under the curve = 533 μg*h/L 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 assessment in patients with unique cardiovascular physiology that may affect drug metabolism.