title: Pharmacokinetics of serelaxin in patients with severe renal impairment or end-stage renal disease requiring hemodialysis: A single-dose, open-label, parallel-group study.
abstract: Serelaxin, a recombinant human relaxin-2 hormone, is in clinical development for treating acute heart failure. This open-label, parallel-group study investigated serelaxin pharmacokinetics (PK) after a single 4-hour intravenous infusion (10 µg/kg) in patients with severe renal impairment (n = 6) or end-stage renal disease (ESRD) requiring hemodialysis (PK on the day of dialysis [n = 6] or during dialysis-free interval [n = 6]), compared with matched healthy subjects (n = 18). In all participants, serum serelaxin concentration peaked at the end of infusion and subsequently declined with mean terminal elimination half-life of 6.5-8.8 hours. Compared with healthy subjects, a moderate decrease in serelaxin systemic clearance (37%-52%) and increase in its exposure (30%-115%) were observed in all patients. During the 4-hour hemodialysis in ESRD patients, 30% serelaxin was removed, with hemodialysis clearance constituting approximately 52% of total systemic clearance. Serelaxin was well tolerated with no deaths, serious adverse events (AE), or AE-related discontinuations. Antiserelaxin antibodies were not detected in any participant. Given the shallow dose-response relationship observed with serelaxin in clinical studies and its wide therapeutic window, the observed PK differences in patients with severe renal impairment compared with healthy subjects are unlikely to pose a safety risk and do not warrant a predefined dosage adjustment in such patients.
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Marion
authors.initials: M
authors.lastname: Dahlke
authors.affiliation: Clinical Research Services GmbH, Kiel, Germany.
authors.forename: Atef
authors.initials: A
authors.lastname: Halabi
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Jasna
authors.initials: J
authors.lastname: Canadi
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Tsubouchi
authors.affiliation: Novartis Healthcare Pvt Ltd, Hyderabad, India.
authors.forename: Surendra
authors.initials: S
authors.lastname: Machineni
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: Yinuo
authors.initials: Y
authors.lastname: Pang
mesh_terms: D005260:Female; D006207:Half-Life; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008875:Middle Aged; D011994:Recombinant Proteins / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012065:Relaxin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006435:Renal Dialysis / Q000379:methods; D051437:Renal Insufficiency / Q000378:metabolism*; D012720:Severity of Illness Index
chemical_list: D011994:Recombinant Proteins; C577649:serelaxin protein, human; D012065:Relaxin
keywords: end-stage renal disease; pharmacokinetics; renal impairment; serelaxin