Influence of hepatic impairment on the pharmacokinetics and pharmacodynamics of landiolol hydrochloride, an ultra-short-acting beta1-blocker

Drugs R D. 2005;6(6):385-94. doi: 10.2165/00126839-200506060-00006.

Abstract

Objective: To investigate the effects of mild to moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of landiolol hydrochloride, a new ultra-short-acting beta1-adrenergic antagonist.

Methods: Six patients with hepatic impairment and six healthy volunteers were enrolled in the open-label, parallel-group study. Landiolol hydrochloride was given intravenously with a 1-minute loading infusion of 0.06 mg/kg/min, followed by a 60-minute infusion of 0.02 mg/kg/min using an automated infusion pump. Venous blood was drawn just before (predose) and 1, 2, 5, 15, 30 and 61 minutes after beginning the continuous intravenous infusion (during infusion); 2, 5, 10 and 30 minutes and 1, 4 and 8 hours after the end of the infusion (after infusion); and 24 hours after beginning the infusion (next day). Urine samples were collected up to 24 hours after beginning the infusion. Before subjects were discharged, an indocyanine green elimination test, clinical laboratory testing, physical examination and recording of ECGs and vital signs were performed.

Results: The geometric mean maximum plasma concentration and area under the concentration-time curve values for the patients with hepatic impairment were 42% and 44% higher, respectively, than those observed for the healthy volunteers, indicating that hepatic impairment affected the disposition of landiolol hydrochloride. There were no significant changes in the elimination half-life of the drug. There were no clinically significant differences between the two groups in terms of reductions in heart rate or blood pressure.

Conclusion: The pharmacokinetic and pharmacodynamic characteristics of this ultra-short-acting beta1-blocker were maintained even in the patients with hepatic impairment. Although we did not observe any drug-related adverse events in these patients, hypotension or bradycardia should be considered, necessitating continuous monitoring of both heart rate and BP in patients with hepatic impairment who receive landiolol hydrochloride.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists* / administration & dosage
  • Adrenergic beta-Antagonists* / pharmacokinetics
  • Adrenergic beta-Antagonists* / pharmacology
  • Aged
  • Female
  • Heart Rate / drug effects*
  • Humans
  • Infusions, Intravenous
  • Liver Diseases / metabolism*
  • Liver Diseases / physiopathology
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Morpholines* / administration & dosage
  • Morpholines* / pharmacokinetics
  • Morpholines* / pharmacology
  • Receptors, Adrenergic, beta-1 / metabolism*
  • Urea / administration & dosage
  • Urea / analogs & derivatives*
  • Urea / pharmacokinetics
  • Urea / pharmacology

Substances

  • Adrenergic beta-Antagonists
  • Morpholines
  • Receptors, Adrenergic, beta-1
  • landiolol
  • Urea