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 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.

WITHDRAWN: A multicenter case-control study on non-genetic risk factors in infants with congenital heart disease

“…20 Many studies have shown that the usage of drugs has certain impact on congenital heart disease, such as anti-infective drugs, sulfonamides have significant impact on the normal development of cardiovascular system, but the relationship between penicillin and congenital heart disease is not certain. 21,22 Antiasthma, antidepressant, antifungal drugs and drugs for treating hypertension and hypothyroidism all increased the incidence of congenital heart disease. 23 Several large-scale studies have shown that pregnant women who took progesterone, amphetamine, anticancer drugs and methionine in the early pregnancy significantly increased the risk of developing CHD in their offspring.…”

Effect of age on the sildenafil impact on the histological and ultra-structure of the liver in male albino rat

“…In the first days of neonatal life, the clearance of sildenafil is about one-third of that seen in adults with increased half-life of 48-56 hours. This could be explained by immaturity of the cytochrome P450 system, which becomes mature in the first week of life [10].…”

Advances in Pediatric Pharmacology, Therapeutics, and Toxicology

“…Since children with single ventricle heart defects have altered hepatic physiology that might influence drug metabolism, a study was conducted to determine the effect of elevated hepatic pressure on the pharmacokinetics (PK) of sildenafil in this population [11]. A population PK model was developed for 20 children with a median (range) age of 3.2 years (0.8–5.3) receiving single dose intravenous sildenafil during cardiac catheterization.…”

“…Additionally, predicted drug exposure increased in subjects with hepatic pressures ≥10 mmHg compared to <10 mmHg by approximately 1.5 fold (median area under the concentration versus time curve, 533 vs. 792 ug·h/L). As such, the investigators concluded that hepatic pressure should be considered when prescribing sildenafil for children with single ventricular defects [11]. …”