Pharmacokinetics and Pharmacodynamics of Low-, Intermediate-, and High-Dose Landiolol and Esmolol During Long-Term Infusion in Healthy Whites

Abstract

The pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of esmolol and landiolol, a new fast-acting cardioselective β-blocker, were compared for the first time in Caucasian subjects in a prospective clinical trial. Twelve healthy volunteers received landiolol and esmolol by continuous infusion for 24 hours in a randomized crossover study using a dose-escalation regimen. Blood concentrations of drugs and metabolites, heart rate, blood pressure, ECG parameters, and tolerability were observed for 30 hours and compared. Drug blood concentrations and areas under the curve were dose-proportional. The half life of landiolol (4.5 minutes) was significantly shorter than that of esmolol (6.9 minutes). Volume of distribution and total clearance were lower for landiolol. Heart rate reduction was faster and more pronounced with landiolol and retained throughout the administration period; effects on blood pressure were not different. Landiolol turned out to be superior to esmolol with respect to pharmacokinetic and pharmacodynamic profile and local tolerability.

Pharmacodynamic and pharmacokinetic behavior of landiolol during dobutamine challenge in healthy adults

“…This phenomenon was seen before (41) and can be explained by a β2-mediated stimulation of the sinus node which cannot be antagonized by a highly selective β1-receptor antagonist. Previous investigations with long-term landiolol infusions had shown stable HR and blood concentrations between 16 and 60 min and thereafter [42]. Similarly, it has been reported previously that dobutamine concentrations in blood are also quite stable during a 60 min infusion [43].…”

“…After initiation of landiolol infusion, the dobutamineinduced HR decreased continuously over the infusion period of one hour, with a substantial part of the pharmacodynamic effect (− 32 bpm) observed already in the early phase (until 16 min) even if landiolol was not administered as a bolus. A rapid onset of the HR-reducing effect had been also seen in the absence of dobutamine in a comparative study versus esmolol [42]. A further slow decrease of HR (− 8 bpm) was observed after 16 min despite the fact that concentrations of landiolol in blood did not change during this steady-state phase.…”

“…Local tolerability was assessed at the start and at the end of β-blocker infusion, and 2 h after the end of infusion as described earlier [42]. For the assessment of safety and tolerability, clinically relevant abnormalities in physical examination, vital signs, ECG, laboratory parameters, as well as local tolerability results and adverse events were assessed or recorded.…”

“…Concentrations of landiolol and its metabolites (LM1, LM2) in supernatants of ethanol-precipitated whole blood were quantitated using a validated HPLC-MS/MS method as described earlier [42]. The lower and upper limits of quantitation with this method are 10 ng/ml and 550 ng/ml, resp., for landiolol and LM2, and 50 ng/ml and 2800 ng/ml, resp., for LM1.…”

Landiolol, an ultra-short acting beta-1 blocker, for preventing postoperative lung cancer recurrence: study protocol for a phase III, multicenter randomized trial with two parallel groups of patients

“…Landiolol hydrochloride (landiolol) is an ultra-short-acting beta-1-selective blocker that has been developed in Japan, whose pharmacokinetics and pharmacodynamics profiles are similar to esmolol [15, 16]. Because it is approved for emergency treatment of intraoperative and postoperative tachyarrhythmia, it is used for supraventricular arrhythmia including atrial fibrillation/flutter (AF) after pulmonary resection for lung cancer treatment [17, 18].…”