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Pharmacology: Pharmacodynamics: Levocetirizine, the active enantiomer of cetirizine, is an antihistamine; its principal effects are mediated via inhibition of H1 receptors. The antihistaminic activity of Levocetirizine has been documented in a variety of animal and human models. In vitro binding studies revealed that Levocetirizine has an affinity for the human H1-receptor, 2-fold higher than that of cetirizine (Ki = 3 nmol/L vs. 6 nmol/L, respectively). The clinical relevance of this finding is unknown.
Pharmacokinetics: Absorption: Levocetirizine is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations are achieved 0.9 hour after dosing. The accumulation ratio following daily oral administration is 1.12 with steady state achieved after 2 days. Peak concentrations are typically 270 ng/mL and 308 ng/mL following a single and a repeated 5 mg once daily dose, respectively. Food has no effect on the extent of exposure (AUC) of the Levocetirizine tablet, but Tmax was delayed by about 1.25 hours and Cmax was decreased by about 36% after administration with a high fat meal; therefore, Levocetirizine can be administered with or without food.
Distribution: The mean plasma protein binding of Levocetirizine in vitro ranged from 91 to 92%, independent of concentration in the range of 90-5000 ng/mL, which includes the therapeutic plasma levels observed. Following oral dosing, the average apparent volume of distribution is approximately 0.4 L/kg, representative of distribution in total body water.
Metabolism: 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 hepatic drug metabolizing 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 involves multiple and/or unidentified CYP isoforms.
Elimination: The plasma half-life in adult healthy subjects was about 8 hours and the mean oral total body clearance for Levocetirizine was approximately 0.63 mL/kg/min. The major route of excretion of Levocetirizine and its 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 clearance of Levocetirizine correlates with that of creatinine clearance. In patients with renal impairment the clearance of Levocetirizine is reduced.
