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

• Published in: Journal of clinical pharmacy and therapeutics Vol. 38; no. 6; pp. 518 - 523
• Main Authors: Peterson, L., Marbury, T., Marier, J., Laliberte, K.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Publishing Ltd 01.12.2013; Blackwell; John Wiley & Sons, Inc
• Subjects: Adult; Antihypertensive Agents - adverse effects; Antihypertensive Agents - pharmacokinetics; Area Under Curve; Biological and medical sciences; Body Mass Index; Body Weight - physiology; Chromatography, High Pressure Liquid; clinical trials; Cohort Studies; Delayed-Action Preparations; Epoprostenol - adverse effects; Epoprostenol - analogs & derivatives; Epoprostenol - pharmacokinetics; Female; Gastroenterology. Liver. Pancreas. Abdomen; Half-Life; Healthy Volunteers; hepatic impairment; Humans; Liver Diseases - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Middle Aged; Other diseases. Semiology; pharmacokinetics; Pharmacology. Drug treatments; Pneumology; pulmonary arterial hypertension; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Tandem Mass Spectrometry; treprostinil; Diolamine; Human; Evaluation; Vasodilator agent; Prostaglandin I2; Respiratory disease; Cardiovascular disease; Hepatic disease; Artery; Pulmonary hypertension; hepatic impairment; Liver failure; Blood vessel; Treprostinil; Digestive diseases; Clinical trial; clinical trials; Circulatory system; Pharmacokinetics; pulmonary arterial hypertension; pharmacokinetics; treprostinil
• ISSN: 0269-4727; 1365-2710; 1365-2710
• DOI: 10.1111/jcpt.12094

Summary What is known and 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. What is new and conclusion Based on these results, dosage adjustments should be performed in subjects with hepatic impairment. The 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. 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. The overall incidence of all AEs and the specific events of headache and nausea increased with severity of hepatic impairment. Based on these results, dosage adjustments should be performed in subjects with hepatic impairment.