Population pharmacodynamic model of bronchodilator response to salbutamol in wheezy preschool children
Thu Thuy Nguyen (1), Francis Amsallem (2), André Denjean (3), Grazia Fenu (4), Paul Seddon (5), France Mentré (1), Corinne Alberti (6,7), Enrico Lombardi (6), Nicole Beydon (8,9)
(1) IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France ; (2) Unité de Pneumologie pédiatrique. CHRU de Montpellier, Montpellier, France ; (3) AP-HP, Service de Physiologie-Explorations Fonctionnelles Respiratoires, Hôpital Robert Debré, Paris, France ; (4) Paediatric Pulmonary Unit, , "Meyer" Paediatric University-Hospital, Florence, Italy ; (5) Respiratory Care, Royal Alexandra Children's Hospital, Brighton, United Kingdom ; (6) AP-HP, Hôpital d'Enfants Robert Debré, Unité d'Epidémiologie Clinique, Paris, France ; (7) INSERM CIE5, Université Paris Diderot, Sorbonne Paris Cité, Paris, France ; (8) AP-HP, Unité Fonctionnelle de Physiologie-Explorations Fonctionnelles Respiratoires, Hôpital d'Enfants Armand-Trousseau, Paris, France; (9) INSERM U938 Centre de Recherche Saint Antoine, Paris, France
Objectives: Inhaled short-acting beta2-agonists such as salbutamol are used to relieve acute symptoms of asthma in clinical settings and to measure airway reactivity during routine lung function testing. Preschool wheezing is a heterogeneous condition characterised by inconsistent effect of asthma medications [1], therefore it is not known whether the dose-response of salbutamol specific of asthma in adults exists in young children. We studied for the first time the population dose-response relationship of salbutamol in preschool wheezers using interrupter resistance (Rint) measurements [2]. A simulation study was performed to determine the appropriate salbutamol dose to administer for this age group.
Methods: Children (3 to 6 years) with wheezing episodes in the previous year were enrolled in a multicenter study. Each child received two successive doses of salbutamol in four groups (100, 400), (100, 600), (200, 600), and (200, 800) µg. Design evaluation was performed using PFIM3.2 [3]. Rint measured after each dose were described with a sigmoid Imax model. Data were analysed by nonlinear mixed models using SAEM algorithm [4] in MONOLIX4.3. A covariate analysis was performed to study the effect of several factors (asthma symptom control, treatment, allergy, tobacco exposure, etc.) using forward selection based on likelihood ratio test. Using the final model, individual Rint values (expressed in % of the expected Rint for a given height [5]) were simulated for 5000 children at progressive doses from 0 to 800 µg. We predicted at each dose the proportion of children with significant Rint reversibility (decrease ≥35% of predicted Rint).
Results: Data from 99 children were available for analysis. The Imax model adequately fitted the data with satisfactory goodness-of-fit plots. Children with uncontrolled symptoms had lower Imax compared to those with totally or partly controlled symptoms (0.23 vs 0.31, p<0.001). Dose to reach 50% of Imax (D50) was 51 µg. According to simulation, 88.1% of children with significant reversibility at 800 µg would already show significant reversibility at 400 µg.
Conclusions: Interrupter resistance could measure a dose-response curve to salbutamol in wheezy preschool children, which was similar to that of older patients. These young children require a high dose of salbutamol to correctly assess airway bronchodilator response (at least 400 µg). Poor symptom control was associated with reduced bronchodilation.
References:
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