Pharmacokinetics, Tolerability, and Safety of Single and Multiple Omecamtiv Mecarbil Doses in Healthy Japanese and Caucasian Subjects

• Published in: European journal of drug metabolism and pharmacokinetics Vol. 46; no. 6; pp. 759 - 770
• Main Authors: Trivedi, Ashit, Malik, Fady I., Mackowski, Mia, Hutton, Shauna, Aoki, Makoto, Abbasi, Siddique, Dutta, Sandeep, Lee, Edward
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.11.2021
• Subjects: Administration, Oral; Adult; Area Under Curve; Asians; Biological Availability; Biomedical and Life Sciences; Biomedicine; Female; Half-Life; Healthy Volunteers; Human Physiology; Humans; Japan; Male; Medical Biochemistry; Original Research Article; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Pharmacy; Tablets - adverse effects; Tablets - pharmacokinetics; Urea - adverse effects; Urea - analogs & derivatives; Urea - pharmacokinetics; Japan
• ISSN: 0378-7966; 2107-0180; 2107-0180
• DOI: 10.1007/s13318-021-00711-2

Background and Objectives Omecamtiv mecarbil (OM) is a cardiac myosin activator under development for the treatment of heart failure. The pharmacokinetics of single and multiple doses of OM were investigated in healthy Japanese subjects in two clinical studies. Methods Study 1 ( n = 36) evaluated the bioavailability and pharmacokinetics after intravenous infusion (15 mg/h for 4 h) and an oral modified release (MR) tablet in healthy Japanese and Caucasian subjects using 25 mg single and multiple doses and 50 mg single dose. Study 2 ( n = 50) evaluated the pharmacokinetics of OM with multiple oral doses of 25 mg MR tablets twice a day (BID) followed by up-titration to either 37.5 mg or 50 mg BID in healthy Japanese subjects. Results In Study 1, the maximum observed plasma concentration ( C max ) and area under the plasma concentration-time curve (AUC) from time 0 to infinity (AUC inf ) in Japanese subjects after a single oral dose of 50 mg were twice that at the 25 mg dose, consistent with that observed in Caucasian subjects. Following single oral doses of 25 mg and 50 mg, absolute bioavailability was 56.5% and 59.2% for Japanese subjects and 63.1 and 83.6% for Caucasian subjects, respectively. No ethnic differences were observed in the pharmacokinetics of OM and its metabolites following single and multiple doses of 25 mg and 50 mg. In Study 2, the mean accumulation ratios based on AUC from 0 to 12 h (AUC 12 ) were approximately four-fold from day 1 to day 8 and from day 20 to day 27 across ethnic groups. The mean ratios of C max to predose concentrations ( C predose ) ranged from 1.25 to 1.38 across subgroups. Conclusions OM showed consistent and predictable pharmacokinetics after multiple dosing in Japanese subjects.