title: Pharmacokinetics of serelaxin in patients with hepatic impairment: a single-dose, open-label, parallel group study.
abstract: OBJECTIVE
  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.
authors.affiliation: Peoples Friendship University of Russia, Moscow, Russia.
authors.forename: Zhanna
authors.initials: Z
authors.lastname: Kobalava
authors.affiliation: Peoples Friendship University of Russia, Moscow, Russia.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Villevalde
authors.affiliation: Peoples Friendship University of Russia, Moscow, Russia.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Kotovskaya
authors.affiliation: Gastroenterologisch-Hepatologisches Zentrum Kiel, Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Hinrichsen
authors.affiliation: Clinical Research Services, Kiel, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Petersen-Sylla
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zaehringer
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: Yinuo
authors.initials: Y
authors.lastname: Pang
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Iris
authors.initials: I
authors.lastname: Rajman
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Jasna
authors.initials: J
authors.lastname: Canadi
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Marion
authors.initials: M
authors.lastname: Dahlke
authors.affiliation: KinDyn Consulting Ltd, Horsham, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Lloyd
authors.affiliation: Clinical Research Services, Kiel, Germany.
authors.forename: Atef
authors.initials: A
authors.lastname: Halabi
mesh_terms: D019540:Area Under Curve; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D005858:Germany; D006801:Humans; D007262:Infusions, Intravenous; D008099:Liver / Q000378:metabolism* / Q000503:physiopathology; D008107:Liver Diseases / Q000097:blood / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D012065:Relaxin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D012426:Russia; D012720:Severity of Illness Index
chemical_list: D002317:Cardiovascular Agents; D011994:Recombinant Proteins; C577649:serelaxin protein, human; D012065:Relaxin
keywords: cardiovascular disease; healthy subjects; hepatic; pharmacokinetics; therapeutics