Treprostinil Attains Clinically Therapeutic Concentrations in Neonates with Pulmonary Hypertension on Extracorporeal Membrane Oxygenation Support

Abstract

Background: Treprostinil is a prostacyclin analog used for treatment of pulmonary hypertension (PH) in adults and children, currently awaiting clinical assessment for use in neonates.Objectives: We aimed to investigate the use of treprostinil in neonates with PH on extracorporeal membrane oxygenation (ECMO) support and measure plasma concentrations of the drug.Methods: This is a retrospective case‐series with prospectively collected blood samples, conducted in a quaternary care neonatal intensive care unit. Brain natriuretic peptide, cardiac function on Doppler echocardiography, and the occurrence of adverse effects was monitored. Plasma concentrations were measured using high‐performance liquid chromatography and mass spectrometry.Results: Four patients with PH requiring ECMO therapy were studied. Treprostinil doses of 20–58 ng/kg/min reached concentrations of 0.99–4.39 ng/ml and induced clinical improvement. Infusion of treprostinil was associated with improved right ventricular function, reversed right‐to‐left shunting through the ductus arteriosus, and stable or decreasing need for vasopressor support. No adverse effects were observed.Conclusions: This is the first study to report clinically therapeutic treprostinil concentrations in circulating plasma after treprostinil administration in neonates on ECMO, with associated clinical improvement of PH and no signs of hemodynamic instability.

Pharmacokinetics of treprostinil in children with functional single-ventricle pulmonary arterial hypertension: a randomized controlled trial

“…Overall, 12 clinical trials on treprostinil for children with PH were registered on the clinical trial registries from the World Health Organization network (16). According to previous reports, TRE therapy is safe and efficacious in pediatric CHD patients with PAH (17)(18)(19). Intravenous (IV) or subcutaneous (SC) administration are two available options for continuous TRE use (13).…”

“…Several studies have reported the therapeutic effect of TRE in pediatric patients with PAH, but documented results of TRE in pediatric patients with FSV-PAH are lacking. The goal dose of TRE was approximately 20 ng/kg/min in many studies (18,21). De Bie et al reported TRE concentrations during clinical treatment in four neonates on extracorporeal membrane oxygenation support (18).…”

“…The goal dose of TRE was approximately 20 ng/kg/min in many studies (18,21). De Bie et al reported TRE concentrations during clinical treatment in four neonates on extracorporeal membrane oxygenation support (18). The starting dose of TRE was 4 ng/kg/min and was gradually increased by 4 ng/kg/min every 8 hours aiming for a dose of 20 ng/kg/min (18).…”

“…De Bie et al reported TRE concentrations during clinical treatment in four neonates on extracorporeal membrane oxygenation support (18). The starting dose of TRE was 4 ng/kg/min and was gradually increased by 4 ng/kg/min every 8 hours aiming for a dose of 20 ng/kg/min (18). Finally, TRE doses ranging from 20 to 58 ng/kg/min reached concentrations of 0.99-4.39 ng/mL in these neonates with PAH and resulted in clinical improvement (18).…”

“…The starting dose of TRE was 4 ng/kg/min and was gradually increased by 4 ng/kg/min every 8 hours aiming for a dose of 20 ng/kg/min (18). Finally, TRE doses ranging from 20 to 58 ng/kg/min reached concentrations of 0.99-4.39 ng/mL in these neonates with PAH and resulted in clinical improvement (18). Levy et al found that the average stable dose of SC TRE in children with severe PAH was 55 ng/kg/min with a range of 15-350 ng/kg/min (17).…”