title: Evaluation of pharmacokinetic and pharmacodynamic profiles and tolerability after single (2.5, 5, or 10 mg) and repeated (2.5, 5, or 10 mg bid for 4.5 days) oral administration of ivabradine in healthy male Korean volunteers.
abstract: BACKGROUND
  Ivabradine, a selective inhibitor of the pacemaker current in the sinoatrial node, has shown pure heart rate (HR)-reducing effects with anti-ischemic efficacy as well as improvement in heart failure outcomes.
  
  
  OBJECTIVE
  The purpose of this study was to explore pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and tolerability in healthy male Korean volunteers, as well as to compare them with PK/PD profiles of white subjects.
  
  
  METHODS
  This was a randomized, double-blind, placebo-controlled Phase I study conducted in healthy male subjects. For each of the 3 dosing groups, 9 subjects were randomized to receive ivabradine and 3 to receive placebo. Subjects received a single oral dose of ivabradine 2.5, 5, or 10 mg and after a 3-day washout period, repeat doses of 2.5, 5, or 10 mg BID for 4.5 days. Blood and urine samples were collected over 72 hours during each period, and levels of ivabradine and its metabolite S18982 were determined by using validated LC-MS/MS, followed by noncompartmental PK analysis. For PD properties and tolerability, 24-hour Holter recordings were obtained: at baseline, after a single dose, after repeated doses, and after the last dose. Serial resting 12-lead ECG assessments were also performed throughout the study.
  
  
  RESULTS
  Forty-eight subjects were enrolled, and 45 completed the study. After single doses of 2.5, 5, and 10 mg, respective mean Cmax levels of ivabradine were 9, 15, and 39 ng/mL, and mean AUC0-last values were 30, 52, and 121 ng h/mL. At steady state, mean Cmax,ss levels were 11, 19, and 42 ng/mL, reached at a median Tmax of 0.67 hour for all 3 doses. The mean AUC0-τ levels were 43, 58, and 139 ng h/mL, respectively. The PK findings were linear with dose and time. Decreases in mean HR on both the Holter recordings and ECGs were observed in all of the ivabradine groups compared with placebo. After the repeated doses, mean decreases in HR were greater than those for the single doses for the same period. Statistically significant differences were observed between the 5- and 10-mg ivabradine groups and placebo. A total of 3 adverse events were reported in 2 subjects receiving ivabradine; both fully recovered without sequelae.
  
  
  CONCLUSIONS
  Single and repeated administration of ivabradine were generally well tolerated in these healthy male Korean volunteers. Ivabradine induced significant reductions in HR, especially at doses of 5 and 10 mg. PK/PD characteristics were similar to those found in white subjects, suggesting that the dose concentration-response relationship of ivabradine is similar between Korean and white subjects.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Korea.
authors.forename: Hee Youn
authors.initials: HY
authors.lastname: Choi
authors.forename: Yook-Hwan
authors.initials: YH
authors.lastname: Noh
authors.forename: Sang-Heon
authors.initials: SH
authors.lastname: Cho
authors.forename: Jong-Lyul
authors.initials: JL
authors.lastname: Ghim
authors.forename: Sangmin
authors.initials: S
authors.lastname: Choe
authors.forename: Un-Jib
authors.initials: UJ
authors.lastname: Kim
authors.forename: Jin
authors.initials: J
authors.lastname: Ah Jung
authors.forename: Kyun-Seop
authors.initials: KS
authors.lastname: Bae
authors.forename: Hyeong-Seok
authors.initials: HS
authors.lastname: Lim
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D044466:Asian People; D001552:Benzazepines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D000077550:Ivabradine; D008297:Male; D014838:Volunteers; D055815:Young Adult
chemical_list: D001552:Benzazepines; D000077550:Ivabradine