Levozal Mechanism of Action

Pharmacotherapeutic group: antihistamine for systemic use, piperazine derivatives. ATC code: R06A E09.
Pharmacology: Pharmacodynamics: Mechanism of action: 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 = 3.2nmol/l). Levocetirizine has an affinity 2-fold higher than that of cetirizine (Ki = 6.3nmol/l). Levocetirizine dissociates from H₁-receptors with a half-life of 115 ± 38 min.
After single administration, levocetirizine shows a receptor occupancy of 90% at 4 hours and 57% at 24 hours.
Published data of pharmacodynamic studies in healthy volunteers demonstrate that, at half the dose, levocetirizine has comparable activity to cetirizine, both in the skin and in the nose.
Available published data comparing the effects of levocetirizine 5 mg, desloratadine 5 mg, and placebo on histamine-induced wheal and flare, indicates that levocetirizine treatment resulted in significantly decreased wheal and flare formation which was highest in the first 12 hours and lasted for 24 hours, (p<0.001) compared with placebo and desloratadine.
The onset of action of levocetirizine 5 mg in controlling pollen-induced symptoms has been observed at 1 hour post-drug intake in placebo-controlled trials in the model of the allergen challenge chamber.
Available data of in vitro studies (Boyden chambers and cell layers techniques) show that levocetirizine inhibits eotaxin-induced eosinophil transendothelial migration through both dermal and lung cells. Published data from a pharmacodynamic experimental study in vivo (skin chamber technique) showed three main inhibitory effects of levocetirizine 5 mg in the first 6 hours 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.
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. In adults, peak plasma concentrations are achieved 0.9 hour after dosing. Steady state is 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 is available in humans, neither concerning the passage of levocetirizine through the blood-brain barrier. In rats and dogs, the highest tissue levels, are found in liver and kidneys, the lowest in the central nervous system (CNS) compartment. 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.
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 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 CYP3A4 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 hr. The half-life is shorter in small children. The mean apparent total body clearance in adults 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 faeces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.
Special patient populations: Children: Data from a paediatric pharmacokinetic study with oral administration of a single dose of 5 mg levocetirizine in 14 children age 6 to 11 years with body weight ranging between 20 and 40 kg show that C_max and AUC values are about 2-fold greater than that reported in healthy adult subjects in a cross-study comparison. The mean C_max was 450 ng/mL, occurring at a mean time of 1.2 hours, weight-normalised, total body clearance was 30% greater, and the elimination half-life 24% shorter in this paediatric population than in adults.
Elderly: Limited pharmacokinetic data are available in elderly subjects.
Following once daily repeat oral administration of 30 mg levocetirizine for 6 days in 9 elderly subjects (65-74 years of age), the total body clearance was approximately 33% lower compared to that in younger adults. The disposition of racemic cetirizine has been shown to be dependent on renal function rather than on age. This finding would also be applicable for levocetirizine, as levocetirizine and cetirizine are both predominantly excreted in urine. Therefore, the levocetirizine dose should be adjusted in accordance with renal function in elderly patients.
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 hours haemodialysis procedure was <10%.
Hepatic impairment: The pharmacokinetics of levocetirizine in hepatically impaired subjects have not been tested. Patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis) given 10 or 20 mg of the racemic compound cetirizine as a single dose had a 50% increase in half-life along with a 40% decrease in clearance compared to healthy subjects.
Other patient characteristics: Gender: Pharmacokinetic results for 77 patients (40 men, 37 women) were evaluated for potential effect of gender. The half-life was slightly shorter in women (7.08 ± 1.72 hr) than in men (8.62 ± 1.84 hr); however, the body weight-adjusted oral clearance in women (0.67 ± 0.16 mL/min/kg) appears to be comparable to that in men (0.59 ± 0.12 mL/min/kg). The same daily doses and dosing intervals are applicable for men and women with normal renal function.
Race: The effect of race on levocetirizine has not been studied. As levocetirizine is primarily renally excreted, and there are no important racial differences in creatinine clearance, pharmacokinetic characteristics of levocetirizine are not expected to be different across races. No race-related differences in the kinetics of racemic cetirizine have been observed.