ABSTRACT
OBJECTIVE: To assess the pharmacokinetics (PK), safety, and tolerability of siponimod and major metabolites in subjects with mild, moderate, and severe hepatic impairment (HI) compared with demographically-matched healthy subjects (HS). METHODS: This open-label, parallel-group study enrolled 40 subjects (each HI group, n = 8; HS group, n = 16). A staged design was employed starting with the enrollment of subjects with mild HI, followed by those with moderate and severe HI. All subjects received single oral doses of 0.25 mg siponimod on day 1; PK and safety data were collected during the 21-day follow-up. RESULTS: All subjects had similar baseline characteristics and completed the study. No significant differences were observed in the plasma exposure of siponimod in mild, moderate, and severe HI groups vs. HS: Cmax changed by 16%, -13%, and -16%; AUC by 5%, -13%, and 15%, respectively. The unbound siponimod PK parameters vs. HS were similar in the mild HI, and increased in the moderate (Cmax, 15%; AUC, 17%) and severe HI groups (Cmax, 11%; AUC, 50%). Exposure of M3 and M5 also showed 2- to 5-fold increase, particularly in the moderate and severe HI groups vs HS. There were no clinically-relevant safety findings. CONCLUSIONS: Single oral doses of 0.25 mg siponimod were well tolerated, and HI did not significantly alter exposure to siponimod. Increase in the M3 and M5 metabolites requires further evaluation. These results do not warrant any dose adjustments of siponimod in subjects with HI.â©.
Subject(s)
Azetidines/adverse effects , Azetidines/pharmacokinetics , Benzyl Compounds/adverse effects , Benzyl Compounds/pharmacokinetics , Hepatic Insufficiency/metabolism , Liver/drug effects , Administration, Oral , Adolescent , Adult , Aged , Area Under Curve , Azetidines/blood , Azetidines/metabolism , Benzyl Compounds/blood , Benzyl Compounds/metabolism , Female , Half-Life , Hepatic Insufficiency/blood , Hepatic Insufficiency/diagnosis , Humans , Liver/metabolism , Male , Middle Aged , Receptors, Lysosphingolipid/metabolism , Severity of Illness Index , Young AdultABSTRACT
AIMS: Serelaxin is a recombinant form of human relaxin-2 in development for treatment of acute heart failure. This study aimed to evaluate the pharmacokinetics (PK) of serelaxin in patients with hepatic impairment. Secondary objectives included evaluation of immunogenicity, safety and tolerability of serelaxin. METHODS: This was an open-label, parallel group study (NCT01433458) comparing the PK of serelaxin following a single 24 h intravenous (i.v.) infusion (30 µg kg(-1) day(-1) ) between patients with mild, moderate or severe hepatic impairment (Child-Pugh class A, B, C) and healthy matched controls. Blood sampling and standard safety assessments were conducted. Primary non-compartmental PK parameters [including area under the serum concentration-time curve AUC(0-48 h) and AUC(0-∞) and serum concentration at 24 h post-dose (C24h )] were compared between each hepatic impairment group and healthy controls. RESULTS: A total of 49 subjects (including 25 patients with hepatic impairment) were enrolled, of which 48 subjects completed the study. In all groups, the serum concentration of serelaxin increased over the first few hours of infusion, reached steady-state at 12-24 h and then declined following completion of infusion, with a mean terminal half-life of 7-8 h. All PK parameter estimates were comparable between each group of patients with hepatic impairment and healthy controls. No serious adverse events, discontinuations due to adverse events or deaths were reported. No serelaxin treatment-related antibodies developed during this study. CONCLUSIONS: The PK and safety profile of serelaxin were not affected by hepatic impairment. No dose adjustment is needed for serelaxin treatment of 48 h i.v. infusion in patients with hepatic impairment.
