Retrospective population pharmacokinetics of levocetirizine in atopic children receiving cetirizine:: the ETAC® study

Aims To evaluate the population pharmacokinetics of levocetirizine in young children receiving long-term treatment with cetirizine. Methods Data were available from a randomized, double-blind, parallel group and placebo-controlled study of cetirizine in 343 young children between 12 and 24 months of age at entry, who were at high risk of developing asthma, but were not yet affected (ETAC(R) study). Infants received oral drops of cetirizine at 0.25 mg kg(-1) twice daily for 18 months. Plasma concentration of the active enantiomer levocetirizine was determined in blood samples collected at months 3, 12 and 18 (1-3 samples per child). A one-compartment open model was fitted to the data using nonlinear mixed effects modelling (NONMEM). The influence of weight, age, gender, BSA and other covariates on CL/F and V/F was evaluated. Results CL/F increased linearly with weight by 0.044 l h(-1) kg(-1) over an intercept of 0.244 l h(-1), and V/F increased linearly with weight by 0.639 l kg(-1). Population estimates in children with weights of 8 and 20 kg were 0.60 and 1.13 l h(-1) for CL/F, and 5.1 and 12.8 l for V/F, respectively, with interpatient variabilities of 24.4% and 14.7%. Weight-normalized estimates of CL/F and V/F were higher than in adults. The estimated relative bioavailability was 0.28 in 12% of instances of suspected noncompliance. Levocetirizine pharmacokinetics were not influenced by severe allergy or aeroallergen sensitization. Results on the effects of concomitant medications or diseases were inconclusive due to limited positive cases. AUC(ss), calculated in compliant subjects using posterior estimates of the final model, was 1952 (1227-3319) mug l(-1) h (mean, min-max), a value similar to that in adults after intake of 5 mg oral solution (2036 (1414-2827) mug l(-1) h. Conclusions The model suggests that administration of levocetirizine 0.125 mg kg(-1) twice daily in children 12-48 months of age or weighing 8-20 kg yields the same exposure as in adults taking the recommended dose of 5 mg once daily.