u-62840 and Liver-Diseases

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary arterial pressure, resulting in right ventricular overload, right heart failure and eventually death. Treprostinil is a prostacyclin analogue that is used in the treatment of PAH. As an orphan drug, limited information is available regarding its disposition and its use in special populations such as elderly, paediatric and pregnant patients. The objective of the current study was to develop a robust physiologically based pharmacokinetic (PBPK) model for treprostinil intravenous injection and extended-release tablet as the first step to optimize treprostinil pharmacotherapy in patients.. PBPK model was built using Simcyp simulator which integrated physicochemical properties, observed or predicted parameters for drug absorption, distribution and elimination for treprostinil, and population specific physiological characteristics. Three clinical trials after intravenous infusion and nine studies after oral administration of treprostinil extended-release tablet in healthy volunteers were used to develop and validate the model. The simulated PK profiles were compared with the observed data. Extrapolation of the model to patient populations including patients with hepatic impairment was conducted to validate the predictions.. Most of the observed data were within the 5. Predicted absorption, distribution, and metabolic enzyme kinetics gave an insight into the disposition of treprostinil in humans. Extrapolation of the established model to patient populations with hepatic impairment successfully documented the model reliability. The developed model has the potential to be used in the PK predictions in other special patient populations with different demographic, physiological and pathological characteristics.

Topics: Administration, Oral; Aged; Antihypertensive Agents; Child; Epoprostenol; Female; Humans; Injections, Intravenous; Liver Diseases; Models, Biological; Pregnancy; Reproducibility of Results; Tablets

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.. 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.. Based on these results, dosage adjustments should be performed in subjects with hepatic impairment.

Topics: Adult; Antihypertensive Agents; Area Under Curve; Body Mass Index; Body Weight; Chromatography, High Pressure Liquid; Cohort Studies; Delayed-Action Preparations; Epoprostenol; Female; Half-Life; Healthy Volunteers; Humans; Liver Diseases; Male; Middle Aged; Tandem Mass Spectrometry