Open-Label Two-Dose Pilot Study of Landiolol for the Treatment of Atrial Fibrillation/Atrial Flutter in Caucasian Patients.

BACKGROUND: We investigated for the first time the suitability of landiolol, an ultra-short-acting ß1-specific ß-blocker, for the treatment of atrial fibrillation/atrial flutter (AF/AFL) in Caucasian patients.Methods and Results:The 20 study patients received landiolol as a continuous infusion (starting dose 40 µg/kg/min) with (B+CI) or without (CI) a preceding bolus dose (100 µg/kg/min administered over 1 min) in a prospective open-label study. The primary endpoint was the proportion of patients with sustained heart rate (HR) reduction ≥20% or to <90 beats/min within 16 min of starting the CI. Secondary endpoints were the pharmacodynamics, pharmacokinetics, AF/AFL symptoms, safety and tolerability of landiolol. At 16 min, HR was reduced in all patients treated with landiolol. The primary endpoint was met by 60% of patients in the CI group and 40% in the B+CI group without a significant group difference. Overall reduction of AF/AFL symptoms at 16 min was 72%. Safety and local tolerability of landiolol were excellent, and no serious adverse events occurred. CONCLUSIONS: Continuous infusion of landiolol with a starting dose of 40 µg/kg/min is suitable for the acute treatment of tachycardic AF/AFL in Caucasian patients. Administration of a preceding bolus seems unnecessary.

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

The pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of esmolol and landiolol, a new fast-acting cardioselective ß-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 -kinetic Behavior of Low-, Intermediate-, and High-Dose Landiolol During Long-Term Infusion in Whites.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of landiolol, a fast-acting cardioselective ß-blocker, were investigated for the first time in white subjects in a prospective clinical trial. Blood concentrations of landiolol and its metabolites, heart rate (HR), blood pressure (BP), and electrocardiogram parameters were studied in 12 healthy volunteers receiving continuous infusions of a new 12-mg/mL formulation of landiolol using a dose-escalation regimen (10 µg/kg BW/min for 2 hours, 20 µg/kg BW/min for 2 hours, 40 µg/kg BW/min for 20 hours, 6 hours follow-up). Landiolol blood concentrations were dose proportional. Time until steady state decreased with increasing doses. Pharmacokinetic parameters were t1/2 = 4.5 minutes, VD = 366 mL/kg, and total body clearance = 53 mL·kg·min. Maximal blood concentrations of the inactive main metabolite M1 were 10-fold higher than those of landiolol, with t1/2 = 126 minutes, VD = 811 mL/kg, and total body clearance = 4.5 mL·kg·min. HR reduction from baseline was fast (significant after 16 minutes) and sustained throughout the administration period. Systolic and diastolic BP reductions and electrocardiogram parameter changes were less pronounced and became significant only occasionally. Recovery after discontinuation of infusion was fast with little (HR) or no (BP) rebound. The new formulation showed excellent local and general tolerability.

Blood Pressure Recovery After Dobutamine Antagonism: Partial With Landiolol, None With Esmolol.

We investigated the hemodynamic effects of 2 short-acting ß1 -blockers, landiolol and esmolol, in the continuous presence of dobutamine in a prospective, single-center, randomized, crossover study in 16 healthy White volunteers. Dobutamine was infused at a rate sufficient to increase the heart rate by at least 30 beats per minute, followed by a 60-minute infusion of 50 µg/kg/min esmolol or 10 µg/kg/min landiolol on top of the unchanged dobutamine infusion. Concentrations of ß-blockers and their metabolites in blood, heart rate, and blood pressure were followed for 180 minutes. Landiolol reduced the dobutamine-induced heart rate and blood pressure increases better than esmolol. After discontinuation of ß-blocker administration, heart rate recovered swiftly to preinfusion values in both study arms. Systolic and diastolic blood pressure recovered partially after landiolol but showed a continued reduction after esmolol. No serious adverse events were observed. The heart rate effect is characteristic for ß-blockers, whereas the blood pressure effects are likely due to direct and indirect ß-blocker effects as well as influences on various ion channels. This may explain why landiolol that is devoid of effects on renin and sodium, calcium, and potassium channels behaves different from esmolol with respect to blood pressure recovery.

Dobutamine Alters the Pharmacokinetic and Pharmacodynamic Behavior of Esmolol.

Background and objective This study involved an investigation into the pharmacokinetic and pharmacodynamic behavior of esmolol in the presence of dobutamine in healthy subjects of European ancestry. Methods We conducted a single-center, prospective randomized study of 16 healthy subjects with each receiving an infusion of dobutamine sufficient to increase heart rate (HR) by 30 beats per minute (bpm) followed by a 60-minute infusion of 50 µg/kg/min esmolol. Pharmacokinetics, HR, and blood pressure were evaluated for 180 minutes. Results In the presence of dobutamine, esmolol elimination was substantially faster than without dobutamine, Esmolol infusion reduced dobutamine-induced elevation of HR reversibly whereas the dobutamine-induced systolic blood pressure (SBP) reduction did not recover after the termination of the esmolol infusion. No serious adverse events (AEs) were observed. Conclusions The accelerated elimination of esmolol was likely due to higher cleavage through tissue esterases induced by dobutamine-induced increased tissue passage cycles per time unit. The HR effect was characteristic of a beta-blocker, whereas the blood pressure effect was likely due to a mechanism other than direct beta-blockade. HR remained elevated after the infusion of esmolol and dobutamine, most likely due to persistent blood pressure reduction.