Abstract 11985: Sildenafil Pharmacokinetics, Hemodynamic Efficacy and Safety after Stage II Single Ventricle Surgery
Background: Sildenafil is a phosphodiesterase type-5 (PDE-5) inhibitor that mediates pulmonary vasodilation and improves myocardial function in adults with heart failure. These effects may be beneficial after single ventricle surgery but the unique physiology could affect efficacy and pharmacokinetics (PK). We sought to determine sildenafil PK, hemodynamic effect and safety after stage II single ventricle surgery.
Methods: Prospective, dose ranging trial with catheterization and echocardiography performed before and immediately after single dose IV sildenafil (0.125, 0.25, 0.35, or 0.45 mg/kg over 20 minutes). Plasma was collected for non-compartmental PK analysis at 5min, 1, 2, 4 and 18 hours after dosing.
Results: 12 patients were enrolled: median (range) age 1.9 yrs (0.8-4.0), weight 11 kg (8-13), 9 female and 10 with a single right ventricle. Maximum sildenafil concentrations were 235 ± 50, 188 ± 80, 578 ± 136 and 530 ± 347 ng/ml for the respective dosing groups and were above the in vitro threshold needed for 75% PDE-5 inhibition in 10 subjects and 90% inhibition for all 6 subjects with doses ≥ 0.35 mg/kg. Clearance, volume of distribution and elimination half-life were: 0.7 ± 0.3 L/kg/hr, 2.2 ± 1.8 L/kg and 2.7 ± 2.3 hrs respectively. Sildenafil lowered PVR in all 12 subjects (Table) with no dose-response effect. Saturations improved in 6/7 with baseline PVR ≥ 2WU x m² (mean change 4.3%, range 0-16%). Change in saturations correlated with change in PVR (r²=0.75, p<0.01). There was no effect on systolic or diastolic myocardial function. There were no adverse events.
Conclusions: A sildenafil dose of 0.35-0.45mg/kg IV achieved sildenafil concentrations required for maximum PDE-5 inhibition and concentrations were higher than those reported in adults with standard dosing (10mg IV). PK data in this cohort suggests non-linearity in sildenafil disposition. Sildenafil was well tolerated in this small cohort and may be useful after stage II surgery in those with high PVR.
- © 2012 by American Heart Association, Inc.