title: In Vitro Determination of Respimat®Dose Delivery in Children: An Evaluation Based on Inhalation Flow Profiles and Mouth-Throat Models.
abstract: 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 (μg/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.
authors.affiliation: 1 Pharmaceutical Physics Laboratory, Boehringer Ingelheim Pharma GmbH and Co. KG , Ingelheim, Germany .
authors.forename: Deborah
authors.initials: D
authors.lastname: Bickmann
authors.affiliation: 2 Children's Hospital , Evangelisches Krankenhaus Hamm, Germany .
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kamin
authors.affiliation: 3 Clinical Pharmacokinetics, Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH and Co. KG, Ingelheim, Germany .
authors.forename: Ashish
authors.initials: A
authors.lastname: Sharma
authors.affiliation: 1 Pharmaceutical Physics Laboratory, Boehringer Ingelheim Pharma GmbH and Co. KG , Ingelheim, Germany .
authors.forename: Herbert
authors.initials: H
authors.lastname: Wachtel
authors.affiliation: 1 Pharmaceutical Physics Laboratory, Boehringer Ingelheim Pharma GmbH and Co. KG , Ingelheim, Germany .
authors.forename: Petra
authors.initials: P
authors.lastname: Moroni-Zentgraf
authors.affiliation: 4 Children's Hospital, Allergology, Pneumology and Cystic Fibrosis, Goethe-University , Frankfurt am Main, Germany .
authors.forename: Stefan
authors.initials: S
authors.lastname: Zielen
keywords: Respimat Soft Mist™ Inhaler; children; fine particle-fraction; inhalation breathing pattern; inspiratory flow; lung deposition