Source: Health Products Regulatory Authority (ZA) Publisher: Abex Pharmaceutica (Pty) Ltd, Suite C, Rubenstein Ridge, 617 Rubenstein Drive, Moreleta Park, 0181, South Africa
Pharmacotherapeutic group: Antihistamines for systemic use, piperazine derivatives.
ATC code: R06AE09
Pharmacological classification: A 5.7.1 Antihistaminics
Levocetirizine is the R-enantiomer of cetirizine, which is a histamine H1-receptor antagonist. Binding studies revealed that levocetirizine has high affinity for human H1-receptors (Ki = 3,2 nmol/l). Levocetirizine has an affinity 2-fold higher than that of cetirizine (Ki = 6,3 nmol/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.
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.
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.
Levocetirizine is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations are achieved 0,9 hours 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.
No tissue distribution data are 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 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.
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.
The plasma half-life in adults is approximately 8 hours in adults. The half-life is shorter in small children. The mean apparent total body clearance in adults is 0,63 ml/min/kg. The main route of excretion of levocetirizine and metabolites is via urine, accounting for approximately 85% of the dose. Approximately 13% is excreted in the faeces. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.
The pharmacokinetics of levocetirizine are linear with dose- and time-independent with low inter-subject variability.
The apparent body clearance of levocetirizine is correlated to 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 patients, the total body clearance is decreased by approximately 80% when compared to normal patients. The amount of levocetirizine removed during a standard 4-hour haemodialysis procedure was <10%.
Limited pharmacokinetic data are available in elderly subjects. Total body clearance in the elderly is approximately 33% lower compared to younger adults. The disposition of racemic cetirizine has been shown to be dependent on renal function rather than age. This would also be applicable for levocetirizine, as both cetirizine and levocetirizine are both predominantly excreted in urine. Therefore, the dose of levocetirizine should be adjusted in accordance with renal function in elderly patients.
The pharmacokinetics of levocetirizine in hepatically impaired patients 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 patients.
The same daily doses and dosing intervals are applicable for men and women with normal renal function.
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.
In children aged 6 to 11 years with body weight ranging between 20 and 40 kg the Cmax and AUC values are about 2-fold greater than in healthy adults, following oral administration of a single dose of 5 mg levocetirizine. Total body clearance is 30% greater and the elimination half-life 24% shorter in the paediatric population than in adults. Administration of 1,25 mg once daily to children 6 months to 5 years of age is expected to result in plasma concentrations similar to those of adults receiving 5 mg once daily.
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