Pharmacology: Pharmacodynamics: Levocetirizine is the active component of Cetirizine. It is a selective competitive inhibitor for the H1-histamine receptor, both in vitro and in vivo. There is no evidence of any binding with other receptors at concentrations 500 fold higher than those displacing a H1-ligand. It is effective in antagonizing histamine effects in both cutaneous and pulmonary models after IV and PO administration of 0.1-0.2 mg/kg. As with cetirizine safety pharmacology studies indicate a high margin of safety for adverse effects on the CNS, GI, immune and cardiovascular systems. Levocetirizine is unlikely to be involved in torsades de pointes or other arrhythmias. In addition, as levocetirizine is mainly excreted unchanged in man and does not inhibit the major CYP isoforms in human liver microsomes, cardiac and other adverse effects due to pharmacokinetic interactions are also unlikely.
Pharmacokinetics: The pharmacokinetic profile of levocetirizine is linear and time-independent with low inter-subject variability. The clearance of levocetirizine differs slightly in men and women. This difference is clearance, however, does not necessitate the use of a different dose or different dosage intervals in men and women. The pharmacokinetic profiles 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 h after dosing. Steady state is achieved after two days. Peak concentrations are typically 270ng/ml and 308ng/ml following a single and repeated 5 mg o.d. 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 0.41 /kg.
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 is via urine, accounting for a mean of 85.4% of the dose. Excretion via faeces accounts for only 12.9% of the dose. The renal clearance of levocetirizine is close to 30 ml /min/ 1.73m2. When corrected for protein binding the value is about 260ml/min/1.73 m2. Therefore, 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%.