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Background: Aerosol therapy in young children can be difficult. A realistic model based on handling studies and in vitro investigations can complement clinical deposition studies and be used to enable dose-to-the-lung (DTL) predictions. Methods: Predictions on dose delivery to the lung were based on (1) representative inhalation flow profiles from children enrolled in a Respimat® handling study, (2) in vitro measurement of the fine-particle DTL using mouth-throat models derived from nuclear magnetic resonance/computed tomography (NMR/CT) scans of children, and (3) a mathematical model to predict the tiotropium DTL. Accuracy of the prediction was confirmed using pharmacokinetic (PK) data from children with cystic fibrosis enrolled in a phase 3 clinical trial of tiotropium Respimat with valved holding chamber (VHC). Results: Representative inhalation flow profiles for each age group were obtained from 56 children who successfully inhaled a volume >0.15 L from the Respimat with VHC. Average dimensions of the mouth±throat region for 38 children aged 1± < 2 years, 2± < 3 years, 3± < 4 years, and 4± < 5 years were determined from NMR/CT scans. The DTL from the Respimat plus VHC were determined by in vitro measurement and were 5.1 ± 1.1%, 15.6% ± 1.4%, 17.9% ± 1.5%, and 37.1% ± 1.8% of the delivered dose for child models 0± < 2 years, 2± < 3 years, 3± < 4 years, and 4± < 5 years, respectively. This provides a possible explanation for the age dependence of clinical PK data obtained from the phase 3 tiotropium trial. Calculated in vitro DTL per body mass (lg/kg [ ± SD]) were 0.031 ± 0.014, 0.066 ± 0.031, 0.058 ± 0.024, and 0.059 ± 0.029, respectively, compared to 0.046 in adults. Therefore, efficacy of the treatment was not negatively impacted in spite of the seemingly low percentages of the DTL. Conclusions: We conclude that the combination of real-life inhalation profiles with respective mouth±throat models and in vitro determination of delivered DTL is a good predictor of the drug delivery to children via the Respimat with VHC. The data provided can be used to support data from appropriate clinical trials. [ABSTRACT FROM AUTHOR]

Background: Respimat® Soft Mist™ Inhaler (SMI) is a hand-held device that generates an aerosol with a high, fine-particle fraction, enabling efficient lung deposition. The study objective was to assess inhalation success among children using Respimat SMI, and the requirement for assistance by the parent/caregiver and/or a valved holding chamber (VHC). Methods: This open-label study enrolled patients aged <5 years with respiratory disease and history of coughing and/or recurrent wheezing. Patients inhaled from the Respimat SMI (air only; no aerosol) using a stepwise configuration: '1' (dose released by child); '2' (dose released by parent/caregiver), and '3' (Respimat SMI with VHC, facemask, and parent/caregiver help). Co-primary endpoints included the ability to perform successful inhalation as assessed by the investigators using a standardized handling questionnaire and evaluation of the reasons for success. Inhalation profile in the successful handling configuration was verified with a pneumotachograph. Patient satisfaction and preferences were investigated in a questionnaire. Results: Of the children aged 4 to <5 years ( n=27) and 3 to <4 years ( n=30), 55.6% and 30.0%, respectively, achieved success without a VHC or help; with assistance, another 29.6% and 10.0%, respectively, achieved success, and the remaining children were successful with VHC. All children aged 2 to <3 years ( n=20) achieved success with the Respimat SMI and VHC. Of those aged <2 years ( n=22), 95.5% had successful handling of the Respimat SMI with VHC and parent/caregiver help. Inhalation flow profiles generally confirmed the outcome of the handling assessment by the investigators. Most parent/caregiver and/or child respondents were satisfied with operation, instructions for use, handling, and ease of holding the Respimat SMI with or without a VHC. Conclusions: The Respimat SMI is suitable for children aged <5 years; however, children aged <5 years are advised to add a VHC to complement its use. [ABSTRACT FROM AUTHOR]