Abstract 2768: Open-Label, Multicentre, Pharmacokinetic Study of IV Sildenafil in the Treatment of Neonates With Persistent Pulmonary Hypertension of the Newborn (PPHN)
INTRODUCTION. Despite the use of inhaled NO (iNO), PPHN contributes significantly to mortality and morbidity in term and preterm neonates. Inhibition of the cGMP-specific phosphodiesterase is a potential therapeutic modality.
OBJECTIVE. To evaluate the pharmacokinetics, safety, and tolerability of intravenous sildenafil in newborns with PPHN.
METHODS. This was an open-label, dose-escalation trial. Eligible neonates were <72 hours of age, ≥34 weeks gestation, with confirmed PPHN, and an oxygenation index (OI) of ≥15. Sildenafil was delivered by continuous IV infusion for at least 48 hours and up to 7 days. The sildenafil dose was administered in eight ``step up” treatment groups. In the first two groups, dose was determined as a fraction of the adult dose, followed by dose escalation for subsequent groups.
RESULTS. Five centers enrolled 36 neonates with PPHN at 35±17 hours of age; 29 were enrolled already receiving iNO. Pharmacokinetics of sildenafil and its primary metabolite, UK-103320, were characterized by high inter-individual variability. Plasma concentrations ranged from 18.5 to 150 ng/mL, lower than the expected target of 40 to 350 ng/mL. Maturation of sildenafil clearance was observed over time. Mean baseline OI was 27.9±12. No short-term change from baseline OI was noted in the first three cohorts (n=10, initial sildenafil concentrations of 3.7±4.6 ng/mL), but significant improvement in OI (28.7 to 19.3, p=0.0002) was observed after 4 hours of sildenafil in the higher dose cohorts (cohorts 4 – 8, n=26 with initial sildenafil concentrations of 58.4±44.8 ng/mL). Four subjects discontinued sildenafil due to adverse events (hypotension in three, and one due to anomalous pulmonary venous connection). One subject died 2 hours after beginning the drug infusion from bilateral tension pneumothoraces; all other infants survived. One infant required ECMO support. Of the 7 infants who were enrolled prior to need for inhaled nitric oxide, 6 completed treatment and were discharged without the need for iNO or ECMO.
CONCLUSIONS. This is the largest report of sildenafil treatment in critically ill infants with PPHN. Intravenous sildenafil was well tolerated with short-term improvements in oxygenation noted in the cohorts that received higher infusion doses.