Blackwell Publishing Journal Backfiles 1879-2005
Developmental changes during infancy and childhood can affect drug pharmacokinetics (PK), i.e., absorption, distribution, metabolism, and renal excretion. This, in turn, influences optimal dosing, efficacy, and safety. To date, of the 40 H1-antihistamines available worldwide, only 11 have been studied in children using a PK approach. Here, we provide the pediatricians’ perspective on the population PK of levocetirizine, the pharmacologically active enantiomer of cetirizine, in very young children who received oral cetirizine, and describe the factors that influence levocetirizine PK in this population. In a prospective, randomized, double-blind, parallel-group, placebo-controlled study, very young children received oral cetirizine 0.25 mg/kg twice daily for 18 months. Plasma levocetirizine concentrations were measured in timed, sparse blood samples collected at steady-state (3, 12 and 18 months after commencement of treatment) for the purpose of monitoring safety, and levocetirizine population, PK parameters were derived by using non-linear mixed effects modeling. In 343 children (age 14–46 months, body weight 8.2–20.5 kg), a total of 943 blood samples were obtained. Compliance with cetirizine dosing was documented. The population PK model used predicted that with increasing body weight, levocetirizine oral clearance would increase by 0.044 l/h/kg, and levocetirizine volume of distribution would increase by 0.639 l/kg. Levocetirizine PK were not influenced by eosinophilia, sensitization to allergens, allergic disease, gastroenteritis/diarrhea, or concomitant ingestion of other medications. This population PK model predicts that in very young children, the oral clearance of levocetirizine will be rapid and will increase as body weight and age increase, therefore, levocetirizine dosing should be based on body weight and age in this population. Compared with older patients, on a mg/kg basis, relatively higher doses may be needed, and twice-daily dosing may be necessary, as previously reported for the related racemic H1-antihistamine cetirizine.
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