title: An evaluation of the pharmacokinetics of treprostinil diolamine in subjects with hepatic impairment.
abstract: OBJECTIVE
  Treprostinil 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 1 mg dose in subjects with hepatic impairment.
  
  
  METHODS
  Four 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 24 h after dosing interval (AUC0-24) values in subjects with mild, moderate and severe hepatic impairment increased by approximately 2·2-, 4·9- and 7·6-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.
  
  
  CONCLUSIONS
  Based on these results, dosage adjustments should be performed in subjects with hepatic impairment.
authors.affiliation: United Therapeutics Corporation, Research Triangle Park, NC, USA.
authors.forename: L
authors.initials: L
authors.lastname: Peterson
authors.forename: T
authors.initials: T
authors.lastname: Marbury
authors.forename: J
authors.initials: J
authors.lastname: Marier
authors.forename: K
authors.initials: K
authors.lastname: Laliberte
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015992:Body Mass Index; D001835:Body Weight / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D003692:Delayed-Action Preparations; D011464:Epoprostenol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D053719:Tandem Mass Spectrometry
chemical_list: D000959:Antihypertensive Agents; D003692:Delayed-Action Preparations; D011464:Epoprostenol; C427248:treprostinil
keywords: clinical trials; hepatic impairment; pharmacokinetics; pulmonary arterial hypertension; treprostinil