title: Safety and tolerability of serelaxin, a recombinant human relaxin-2 in development for the treatment of acute heart failure, in healthy Japanese volunteers and a comparison of pharmacokinetics and pharmacodynamics in healthy Japanese and Caucasian populations.
abstract: Serelaxin, a recombinant form of the human relaxin-2 hormone, is currently under clinical investigation for treatment of acute heart failure. This double-blind, placebo-controlled, dose-ranging study investigated the effect of Japanese ethnicity on the pharmacokinetics (PK), pharmacodynamics (PD), and safety and tolerability of serelaxin. Japanese healthy subjects (n = 32) received 10, 30, or 100 µg/kg/day of serelaxin, or placebo, administered as a 48-hour intravenous infusion. A Caucasian cohort (n = 8) receiving 30 µg/kg/day open-label serelaxin was included for comparison. In all subjects, serum serelaxin concentrations increased rapidly after the start of infusion, approached steady state as early as 4 hours, and declined rapidly upon treatment cessation. Serum exposure to serelaxin increased with increasing doses. Statistical dose proportionality was shown for AUC(inf) over the entire dose range. A significant increase in estimated glomerular filtration rate from baseline to Day 2 (30 and 100 µg/kg/day) and to Day 3 (10 and 100 µg/kg/day) was observed compared with placebo. Serelaxin was well tolerated by all subjects. In conclusion, PK, PD, and safety profiles of serelaxin were generally comparable between Japanese and Caucasian subjects, suggesting that no dose adjustment will be required in Japanese subjects during routine clinical use of this agent.
authors.affiliation: Novartis Pharma AG, CH-4056 Basel, Switzerland.
authors.forename: Marion
authors.initials: M
authors.lastname: Dahlke
authors.forename: Dik
authors.initials: D
authors.lastname: Ng
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Surendra
authors.initials: S
authors.lastname: Machineni
authors.forename: Sergej
authors.initials: S
authors.lastname: Berger
authors.forename: Jasna
authors.initials: J
authors.lastname: Canadi
authors.forename: Iris
authors.initials: I
authors.lastname: Rajman
authors.forename: Peter
authors.initials: P
authors.lastname: Lloyd
authors.forename: Yinuo
authors.initials: Y
authors.lastname: Pang
mesh_terms: D000208:Acute Disease; D000328:Adult; D044466:Asian People; D002712:Chlorides / Q000652:urine; D003404:Creatinine / Q000097:blood / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006333:Heart Failure / Q000188:drug therapy*; D006400:Hematocrit; D006801:Humans; D007564:Japan; D008297:Male; D009994:Osmolar Concentration; D061214:Patient Safety; D011188:Potassium / Q000652:urine; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D012065:Relaxin / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012964:Sodium / Q000652:urine; D014508:Urea / Q000652:urine; D044465:White People; D055815:Young Adult
chemical_list: D002712:Chlorides; D011994:Recombinant Proteins; C577649:serelaxin protein, human; D014508:Urea; D012065:Relaxin; D012964:Sodium; D003404:Creatinine; D011188:Potassium
keywords: cardiovascular; clinical pharmacology; clinical trials; pharmacodynamics; pharmacokinetics and drug metabolism