Pharmacokinetics of serelaxin in patients with hepatic impairment: a single-dose, open-label, parallel group study

Abstract

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.

Keywords: cardiovascular disease; healthy subjects; hepatic; pharmacokinetics; therapeutics.

© 2014 The British Pharmacological Society.

Figures

Figure 1

Serelaxin serum concentration–time profiles. Data shown as arithmetic mean with standard deviation in linear and semilogarithmic views for groups of patients with mild (A, B), moderate (C, D) and severe (E, F) hepatic impairment compared with healthy controls. The control groups were demographically matched in terms of ethnicity, gender, age and weight. Subjects received a single 24 h i.v. infusion of serelaxin at 30 μg kg−1 day−1. Serum samples were collected at baseline, during the 24 h infusion and up to 48 h after the end of infusion. Serum serelaxin concentration was analyzed by enzyme-linked immunosorbent assay. , mild hepatic impairment (n = 8); , moderate hepatic impairment (n = 8); , severe hepatic impairment (n = 8); , matched healthy controls (n = 8)

Figure 2

Regression analysis of primary pharmacokinetic parameters vs. degree of hepatic impairment. (A) Dose-normalized AUC(0–∞) of serelaxin and (B) dose-normalized C24 h of serelaxin plotted against Child–Pugh score for all subjects with hepatic impairment compared with healthy controls. , mild hepatic impairment (n = 8); , moderate hepatic impairment (n = 8); , severe hepatic impairment (n = 8); , healthy controls (n = 24)