Iñaki Izquierdo (1), Javier Estévez (2,3), Alejandro Doménech (1), Marta Valle (2,3)
(1) Clinical Development Unit Grupo Uriach, SA, Barcelona, Spain; (2) PKPD modeling and simulation, Institut de Recerca HSCSP-IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; (3) Department of pharmacology, Universitat Autonoma de Barcelona, Spain
Background:Rupatadine is a second generation antihistamine H1 and antagonist of PAF approved in Europe for the treatment of allergic rhinitis and skin conditions for which a pediatric solution is under development.
Objectives: (i) To evaluate the population pharmacokinetics (POPPK) of rupatadine oral solution in children 2-5 and 6-11 years of age with rhinitis allergy and (ii) to determine if the currently proposed regimen dose as a function of weight is enough to achieve similar plasma concentrations to those observed in adults older than 12 years.
Methods: A POPPK model was developed. Data from two studies performed in children with rhinitis allergy were analyzed: Study 1, included 11 children, 6-11 years old, a full PK profile in each children was obtained after a single oral dose of rupatadine. Study 2, 4 blood samples were obtained in 44 children, 2-5 years old after 14 and 28 days of treatment. Doses were 5 mg if weight > 25kg, or 2.5 mg if weight 10-25kg. Models were developed using NONMEM (version VI) with FOCE. Compartmental models were used assuming linear processes. The effect of different covariates (age, sex, height, weight and BMI) on the parameters was also evaluated. The final model was validated and further used to simulate plasma concentrations of rupatadine using different dose regimens for children with different weights.
Results: A two-compartment model with first-order absorption and elimination best described the PK of rupatadine in children (2-11 years-old). Weight influenced the clearance of rupatadine according to a linear function. Estimated parameters ( RSE %) were : Lag=0.15h (6), ka=0.49h-1 (12), Vc=118L (37), Vp=3730L (29), Cld=210L/h (19), CL(20kg)=219L. Interindividual variability was estimated for Vc (139%) and CL (39%). Internal validation of the model showed a good predictive interval. Simulations showed that the proposed doses showed similar plasma concentrations previously described in adults ≥ 12 years old.
Conclusions: The population PK analysis of rupatadine in children 2-11 years old follows a bicompartmental disposition with first-order absorption. Rupatadine clearance increases with age. The used range of doses provided similar plasma concentrations to those associated with efficacy and safety in adults ≥ 12 years old.
Reference: PAGE 21 (2012) Abstr 2615 [www.page-meeting.org/?abstract=2615]
Poster: Paediatrics