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

• Published in: Journal of clinical pharmacology 2015-04, Vol.55 (4), p.415-422
• Main Authors: Dahlke, Marion, Ng, Dik, Yamaguchi, Masayuki, Machineni, Surendra, Berger, Sergej, Canadi, Jasna, Rajman, Iris, Lloyd, Peter, Pang, Yinuo
• Format: Article
• Language: English
• Subjects: Acute Disease; Adult; Asian Continental Ancestry Group; cardiovascular; Chlorides - urine; clinical pharmacology; clinical trials; Creatinine - blood; Creatinine - urine; Dose-Response Relationship, Drug; Double-Blind Method; European Continental Ancestry Group; Female; Healthy Volunteers; Heart Failure - drug therapy; Hematocrit; Humans; Japan; Male; Osmolar Concentration; Patient Safety; pharmacodynamics; pharmacokinetics and drug metabolism; Potassium - urine; Recombinant Proteins - adverse effects; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - therapeutic use; Relaxin - adverse effects; Relaxin - pharmacokinetics; Relaxin - therapeutic use; Sodium - urine; Urea - urine; Young Adult
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1002/jcph.433

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 AUCinf 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.