Source: European Medicines Agency (EU)
Pharmacotherapeutic group: Beta-blocking agents, selective
ATC code: C07AB14
Landiolol is a highly selective beta-1-adrenoreceptor antagonist (the selectivity for beta-1-receptor blockade is 255 times higher than for beta-2-receptor blockade) that inhibits the positive chronotropic effects of the catecholamines adrenaline and noradrenaline on the heart, where beta-1-receptors are predominantly located. Landiolol, as other beta-blockers, is thought to reduce the sympathetic drive, resulting in reduction in heart rate, decrease in spontaneous firing of ectopic pacemakers, slowing the conduction and increase the refractory period of the AV node. Landiolol does not exhibit any membrane-stabilizing activity or intrinsic sympathomimetic activity in vitro. In preclinical and clinical studies, landiolol controlled tachycardia in an ultra-short acting manner with a fast onset and offset of action and further demonstrated anti-ischaemic and cardioprotective effects.
Based on the data in published clinical studies, 991 patients with perioperative or paroxysmal supraventricular tachyarrhythmias (SVT) were treated with landiolol. The efficacy endpoint was determined as heart rate reduction and/or conversion to sinus rhythm for the treatment of sinus tachycardia or SVTs. For the prevention of perioperative atrial fibrillation and for the treatment or prevention of adverse hemodynamic and other responses to specific stimuli related to invasive procedures, 3,039 patients were treated with landiolol. Control of heart rate and blood pressure were the main efficacy parameter in these studies. A significant reduction in heart rate or prevention of heart rate surges were observed in landiolol treated patients. From the clinical studies, safety data are available for 1,569 subjects (see section 4.8). In controlled studies, adverse events were observed in 12% of landiolol treated patients (vs. 5.8% treated with placebo, 20.5% with active comparator treatment and 6.1% with no treatment). In uncontrolled studies, the adverse event rate in landiolol treated patients was 16%. In a postmarketing treatment outcome/user survey, 1,257 patients with peri/postoperative SVT (including atrial flutter) were treated with landiolol. The adverse event rate was 8.0%.
The European Medicines Agency has deferred the obligation to submit the results of studies with Rapibloc in one or more subsets of the paediatric population in the treatment or prevention of supraventricular arrhythmias. See section 4.2 for information on paediatric use.
Data on the treatment of supraventricular tachyarrhythmias with landiolol in children is limited and is based on published literature. A continuous infusion at 4 micrograms/kg BW/min of landiolol decreased the heart rate and returned normal sinus rhythm in a 3-month old infant with postoperative junctional ectopic tachycardia (JET).
Four patients between the age of 14 days and 2 years who developed perioperative JET were treated with landiolol. In all patients landiolol administration at a dose ranging from 1.0 to 10.0 micrograms/kg BW/min achieved successful rate control. No adverse events such as bradycardia, hypotension, or hypoglycaemia were encountered.
In a retrospective analysis, 12 patients between the age of 4 days and 5 years diagnosed with postoperative tachyarrhythmias were treated with landiolol (the mean maintenance dose was 6.8 ± 0.9 micrograms/kg BW/min) for heart rate reduction or conversion to sinus rhythm. Tachyarrhythmias were converted to sinus rhythm in 70.0% of the cases and the average time needed to achieve heart rate reduction was 2.3 ± 0.5 hours. Bradycardia was observed in one patient treated with landiolol at a dose of 10 micrograms/kg BW/min.
When administered by continuous intravenous infusion, the concentration of landiolol in blood reached steadystate values about 15 minutes after initiation of administration. Steady-state can also be achieved faster (up to 2-5 minutes) with regimens that use a higher loading dose infused for 1 minute followed by continuous infusion at a lower dosage.
In healthy volunteers, the mean peak plasma concentration of landiolol was 0.294 micrograms/ml following a single landiolol bolus administration of 100 micrograms/kg. The respective steady state plasma levels after 2 h infusion of 10, 20 and 40 micrograms/kg/min were 0.2, 0.4 and 0.8 micrograms/ml, respectively.
Due to the molecular characteristics of landiolol (low molecular weight of approx. 0.5 kDa and low protein binding capacity), no significant reabsorption by active transport via renal uptake transporters OAT1, OAT3 or OCT2 is anticipated.
The volume of distribution of landiolol was 0.3 l/kg-0.4 l/kg following a single bolus administration of 100–300 micrograms/kg or in steady state during a landiolol infusion of 20-80 micrograms/kg/min. Protein binding of landiolol is low (<10%) and dose dependent.
Landiolol is metabolised via hydrolysis of the ester moiety. In vitro and in vivo data suggest that landiolol is mainly metabolised in the plasma by pseudocholinesterases and carboxylesterases. Hydrolysis releases a ketal (the alcoholic component) that is further cleaved to yield glycerol and acetone, and the carboxylic acid component (metabolite M1), which subsequently undergoes beta-oxidation to form metabolite M2 (a substituted benzoic acid). The beta-1-adrenoreceptor blocking activity of landiolol metabolites M1 and M2 is 1/200 or less of the parent compound indicating a negligible effect on pharmacodynamics taking into account the maximum recommended landiolol dose and infusion duration.
Neither landiolol nor the metabolites M1 and M2 showed inhibitory effects on the metabolic activity of different cytochrome P450 molecular species (CYP1A2, 2C9, 2C19, 2D6 and 3A4) in vitro. The cytochrome P450 content was not affected in rats after repeated intravenous administration of landiolol. There are no data on a potential effect of landiolol or its metabolites on CYP P450 induction or time dependent inhibition available.
In humans, the main excretion pathway of landiolol is urine. After intravenous administration, about 75% of the administered dose (54.4% as metabolite M1 and 11.5% as metabolite M2) is excreted within 4 hours. The primary excretion/elimination pathway of landiolol is via urine with a urinary excretion rate for landiolol and its major metabolites M1 and M2 of >99% within 24 hours.
The total body clearance of landiolol was 66.1 ml/kg/min after a single landiolol bolus administration of 100 micrograms/kg, and 57 ml/kg/min in steady state after a 20 hour continuous landiolol infusion of 40 microgams/kg/min. The elimination half-life of landiolol was 3.2 minutes after a single landiolol bolus administration of 100 micrograms/kg, and 4.52 minutes after a 20 hour continuous landiolol infusion of 40 micrograms/kg/min.
Landiolol showed a linear pharmakokinetic – pharmacodynamic (concentration-effect) relationship across the range of the recommended dosages.
The impact of liver function on the pharmacokinetics of landiolol was investigated in six patients with mild to moderate hepatic impairment (5 patients Child-Pugh class A, one patient Child-Pugh class B, mean plasma cholinesterase level -62%) and six healthy volunteers. Patients with hepatic impairment show a reduction in the volume of distribution of landiolol and an increase of landiolol plasma levels by 40%. The half-life and elimination of the drug is not different from healthy adults.
The pharmacokinetics in patients with renal impairment has not been evaluated.
No major differences in the pharmacokinetics of landiolol are observed between a Caucasian and Japanese population.
Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, genotoxicity, toxicity to reproduction and development. In reproductive and development toxicity studies, landiolol did not impair fertility in rats and did not adversely affect embryofetal development up to maternally toxic doses. In a peri- and postnatal development study in rats, decreased body weight gain and decreased survival at 4 days after birth were observed in high-dose F1 pups at maternally toxic doses. This effect is likely not clinically relevant because it occurred after repeated administration.
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