Chemical formula: C₂₅H₃₉N₃O₈ Molecular mass: 509.6 g/mol PubChem compound: 114905
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.
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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