The concentration of landiolol hydrochloride rapidly reached steady state levels, and rapidly dissipated after completion of administration.

Landiolol hydrochloride is a newly developed cardioselective, ultra short-acting beta(1)-adrenergic receptor blocking agent used for perioperative arrhythmia control. The objective of this study was to characterize the population pharmacokinetics of landiolol hydrochloride in healthy male subjects. A total of 420 blood concentration data points collected from 47 healthy male subjects were used for the population pharmacokinetic analysis. NONMEM was used for population pharmacokinetic analysis. In addition, the final pharmacokinetic model was evaluated using a bootstrap method and a leave-one-out cross validation method. The concentration time course of landiolol hydrochloride was best described by a two-compartment model with lag time. The final parameters were total body clearance (CL: 36.6 mL/min/kg), distribution volume of the central compartment (V1: 101 mL/kg), inter-compartmental clearance (16.1 mL/min/kg), distribution volume of the peripheral compartment (55.6 mL/kg), and lag time (0.82 min). The inter-individual variability in the CL and V1 were 21.8% and 46.3%, respectively. The residual variability was 22.1%. Model evaluation by the two different methods indicated that the final model was robust and parameter estimates were reasonable. The population pharmacokinetic model for landiolol hydrochloride in healthy subjects was developed and was shown to be appropriate by both bootstrap and leave-one-out cross validation methods.

BackgroundPersistent postoperative supraventricular tachyarrhythmias (SVTs) increase cardiac burden and aggravate cardiac hemodynamics. Therefore, for patients in unstable conditions after surgery, prompt and sustained control of heart rate is essential. The importance of β-adrenoceptor antagonists (β-blockers) in controlling such postoperative atrial fibrillation or atrial flutter has been established, and the usefulness of ultra-short-acting β1-blockers with high β1 selectivity has been suggested based on their safety and efficacy under such circumstances.ObjectivesOur objectives were to evaluate the effectiveness and safety of landiolol hydrochloride, an ultra-short-acting β1-selective blocker, in the treatment of postoperative SVT in patients with a high risk of myocardial ischemia, or in patients after highly invasive surgery, in a multicenter, randomized, double-blind, placebo-controlled, group-comparative study.MethodsA total of 165 patients were randomly allocated to three groups and received LM or MH doses of landiolol hydrochloride or placebo. LM group: dose L (1-min loading dose at a rate of 0.03 mg/kg/min, followed by a 10-min infusion at 0.01 mg/kg/min) followed by dose M (1-min loading at a rate of 0.06 mg/kg/min, followed by a 10-min infusion at 0.02 mg/kg/min); MH group: dose M followed by dose H (1-min loading dose at a rate of 0.125 mg/kg/min, followed by a 10-min infusion at 0.04 mg/kg/min); placebo (PP) group: dose P (1-min loading dose at a rate of 0 mg/kg/min, followed by a 10-min infusion at 0 mg/kg/min) followed by another round of dose P. If the targeted heart-rate reduction was not obtained at the end of the first 10-min infusion, the higher dose was started. The primary endpoint was the percentage of patients who met the heart-rate reduction criteria (≥20 % reduction and <100 beats/min). The safety endpoint was the incidence of adverse events in each of the three groups.ResultsThe percentages of patients who met the heart-rate reduction criteria (≥20 % reduction and <100 beats/min) were 0.0, 60.4, and 42.0 % in the PP, LM, and MH groups, respectively. There were significant differences in the LM and MH groups relative to the PP group, but there was no significant difference between the LM and MH groups. No significant difference was observed in the incidence of adverse events among the three groups: 29.6 % in the PP group, 45.5 % in the LM group, and 43.1 % in the MH group.ConclusionLandiolol hydrochloride is effective and safe for patients with postoperative SVT.

Backgroundβ-Adrenoceptor antagonists (β-blockers) have been reported to be effective for regulation of heart rate (HR) and restoring sinus rhythm in postoperative atrial fibrillation and atrial flutter, as well as in the prevention of those arrhythmias after open-heart surgery.ObjectivesThe objectives of this study were to evaluate the dose-dependent effects of landiolol, an ultra-short-acting β1-blocker, as well as the effectiveness and safety of the drug in suppressing supraventricular tachyarrhythmias (SVT) in postoperative patients.MethodsLandiolol was administered as a four-dose titration regimen (LL, L, M, and H doses) to postoperative patients who developed SVT. The titration sequence began with a 1-min loading infusion at a rate of 0.015 mg/kg/min, followed by a 10-min continuous infusion at 0.005 mg/kg/min (the LL dose). Infusions at progressively higher doses followed in sequence until 20 % reduction in HR was achieved. The L dose was a 1-min loading infusion at 0.03 mg/kg/min, followed by a 10-min continuous infusion at 0.01 mg/kg/min. The M dose was a 1-min loading infusion at 0.06 mg/kg/min, followed by a 10-min continuous infusion at 0.02 mg/kg/min. The H dose was a 1-min loading infusion at 0.125 mg/kg/min, followed by a 10-min continuous infusion at 0.04 mg/kg/min. The patient was then observed for 30 min to determine the cardiovascular responses to withdrawal of the medication. After completion of this follow-up period, additional maintenance infusion for up to 6 h was permitted if considered necessary by the investigator.ResultsA total of 108 patients were enrolled in this study. The cumulative improvement rates (percentage of patients obtaining ≥20 % reduction in HR) were 11.4, 32.4, 63.1, and 87.3 % at the LL, L, M, and H doses, respectively, demonstrating the dose-dependent effectiveness of landiolol. Additional infusion for up to 6 h was conducted in 16 patients. HR was maintained between 95.5 and 116.8 beats/min during the maintenance period (mean 259.8 min). Landiolol was generally well tolerated, although one patient with sick sinus syndrome developed an approximately 5-s cardiac arrest.ConclusionsThe overall results, including those pertaining to patient safety, demonstrate that landiolol is effective and useful for the treatment of postoperative SVT.