An evaluation of the pharmacokinetics of treprostinil diolamine in subjects with hepatic impairment

What is known and objectiveTreprostinil diolamine (oral treprostinil) is a prostacyclin analogue under evaluation for the treatment for pulmonary arterial hypertension (PAH). This study assessed the pharmacokinetics (PK) and safety of treprostinil following oral administration of a single sustained-release 1mg dose in subjects with hepatic impairment. MethodsFour cohorts, including healthy volunteers, and subjects with mild, moderate and severe hepatic impairment were enrolled. Thirty subjects completed the study. Mean treprostinil clearance values (CL/F) decreased with the severity of hepatic impairment. The decrease in CL/F resulted in a marked increase in exposure levels of treprostinil. Relative to healthy subjects, mean area under the curve from time zero to 24h after dosing interval (AUC(0-24)) values in subjects with mild, moderate and severe hepatic impairment increased by approximately 22-, 49- and 76-fold, respectively. The most frequent adverse events (AEs) exhibited in this study were similar to those seen with prostacyclin and its analogues and with AEs seen in other clinical studies with oral treprostinil (e.g. headache, diarrhoea and nausea). The overall incidence of all AEs and the specific events of headache and nausea increased with severity of hepatic impairment. What is new and conclusionBased on these results, dosage adjustments should be performed in subjects with hepatic impairment.