A comparison of safety and pharmacokinetics of esuberaprost (BPS-314d-MR) in subjects with normal, mild and moderate hepatic impairment

Statement of Purpose, Innovation or Hypothesis: The prostacyclin analog beraprost (BPS) consists of a mixture of four stereoisomers and is available for treatment of pulmonary arterial hypertension in certain Asian countries. The pharmacologically‐active isomer esuberaprost (BPS‐314d‐MR) is undergoing clinical evaluation in a Phase 3 study in the USA and Israel. To understand the pharmacokinetics (PK) and safety of esuberaprost in subjects with hepatic impairment, subjects with impaired and normal hepatic function were studied. Description of Methods and Materials: This was an open‐label, nonrandomized, multi‐center, multipledose, parallel‐group, safety, tolerance and PK study in subjects with normal, Child‐Pugh Class A (mild), and B (moderate) hepatic impairment. Subjects in Child‐Pugh Class C (severe) were not enrolled after an interim PK and safety analyses of the other groups. Demographics of subjects with moderate impairment were matched with normal subjects for age (+/‐ 10 y), body weight (+/‐ 20%), smoking status and gender. Ten subjects were enrolled in each group. One 15 mug tablet of esuberaprost was administered orally four times daily (QID) during waking hours onDays 1‐4. Standard safety and PK parameters were analyzed as shown below. Data and Results: A comparison of PK data from normal subjects revealed that: there was an approximately 1.1‐ and 2.2‐fold increase in the geometric mean AUC0‐t, AUC0‐24 and Cmax; a 25% and 50% decrease in the geometric mean Tmax in the 0‐4 h time interval; and a 7% and 54% decrease in clearance (CL/F) of esuberaprost in mild‐ and moderately‐impaired groups, respectively. Amajority of related treatment emergent adverse events (TEAEs) occurred on the first and second days of dosing and were consistent with prostacyclin treatment‐related symptoms. The most common TEAE during this study was headache, followed by nausea and polyuria. Interpretation, Conclusion or Significance: Based on the PK and safety results of this study, esuberaprost should be used with caution in subjects with mild (Child‐Pugh Class A) or moderate (Child‐Pugh Class B) hepatic impairment under the careful supervision of a qualified physician.