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Pharmacology: Pharmacodynamics: Levocetirizine the (R) enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors. Binding studies revealed that Levocetirizine has high affinity for human H1-receptors (Ki=3.2 nmol L). Levocetirizine dissociates from H1-receptors with half-life of 115±38 min. Pharmacodynamic studies in healthy volunteers demonstrate that, at half the dose, Levocetirizine has comparable activity to cetirizine, both in skin and in the nose. In vitro studies (Boyden chambers and cell layers techniques) show that Levocetirizine inhibits eotaxin-induced eosinophil transendothelial migration through both dermal and lung cells. A pharmacodynamic experimental study in vivo (skin chamber technique) showed three main inhibitory effects of Levocetirizine 5 mg in the first 6 hour of pollen-induced reaction, compared with placebo in 14 adult patients: inhibition of VCAM-1 release, modulation of vascular permeability and a decrease in eosinophil recruitment. Pharmacokinetic/pharmacodynamic relationship: 5 mg Levocetirizine provide a similar pattern of inhibition of histamin-induced wheal and flare than 10 mg cetirizine. As for cetirizine, the action on histamin-induced skin reaction was out of phase with the plasma concentrations. ECGs did not show relevant effects of Levocetirizine on QT interval.
Pharmacokinetics: The pharmacokinetics of Levocetirizine are linear with dose- and time-independent with low inter-subject variability. The pharmacokinetic profile is the same when given as the single enantiomer or when given as cetirizine. No chiral inversion occurs during the process of absorption and elimination.
Absorption: Levocetirizine is rapidly and extensively absorbed following oral administration. Peak plasma concentrations are achieved 0.9 hour after dosing. Steady state achieved after two days. Peak concentrations are typically 270 ng/mL and 308 ng/mL following a single and a repeated 5 mg once daily dose, respectively. The extent of absorption is dose-independent and is not altered-by food, but the peak concentration is reduced and delayed.
Distribution: No tissue distribution data are available in humans. Levocetirizine is 90% bound to plasma proteins. The distribution of Levocetirizine is restrictive, as the volume of distribution is 0.4 l/kg.
Biotransformation: The extent of metabolism of Levocetirizine in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and O-dealkylation, and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involved multiple and/or unidentified CYP isoforms. Levocetirizine had no effect on the activities of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5 mg oral dose. Due to its low metabolism and absence of metabolic inhibition potential, the interaction of levocetirizine with other substances, or vice-versa, is unlikely.
Elimination: The plasma half-life in adults is 7.9±1.9 hours. The mean apparent total body clearance is 0.63 mL/min/kg. The major route of excretion of levocetirizine and metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via feces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.
Renal Impairment: The apparent body clearance of Levocetirizine is correlated to the creatinine clearance. It is therefore recommended to adjust the dosing intervals of Levocetirizine, based on creatinine clearance in patients with moderate and severe renal impairment. In anuric end stage renal disease subjects, the total body clearance is decreased by approximately 80% when compared to normal subjects. The amount of Levocetirizine removed during a standard 4-hour hemodialysis procedure was <10%.
