Deborah Bickmann1, Wolfgang Kamin2, Ashish Sharma3, Herbert Wachtel1, Petra Moroni-Zentgraf1, Stefan Zielen4. 1. 1 Pharmaceutical Physics Laboratory, Boehringer Ingelheim Pharma GmbH and Co. KG , Ingelheim, Germany . 2. 2 Children's Hospital , Evangelisches Krankenhaus Hamm, Germany . 3. 3 Clinical Pharmacokinetics, Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH and Co. KG, Ingelheim, Germany . 4. 4 Children's Hospital, Allergology, Pneumology and Cystic Fibrosis, Goethe-University , Frankfurt am Main, Germany .
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.
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: B L Laube; H M Janssens; F H C de Jongh; S G Devadason; R Dhand; P Diot; M L Everard; I Horvath; P Navalesi; T Voshaar; H Chrystyn Journal: Eur Respir J Date: 2011-02-10 Impact factor: 16.671
Authors: Stefan Zielen; Gianna Reichert; Helena Donath; Jordis Trischler; Johannes Schulze; Olaf Eickmeier; Martin Eckrich; Katharina Blumchen Journal: J Asthma Allergy Date: 2021-01-14