Kongress / 10.10.2019 - 13.10.2019
Treffen Sie uns auf dem 19. EUSAAT-Jahreskongress
Der 19. Jahreskongress der europäischen Gesellschaft für Alternativen zum Tierversuch (EUSAAT) findet vom 10. bis 13. Oktober 2019 an der Universität Linz (Österreich) statt. Im Fokus des diesjährigen EUSAAT-Kongresses stehen alle Bereiche der Lebenswissenschaften, in denen Versuchstiere eingesetzt werden, wie etwa die Pharma-, Kosmetik- und Chemieindustrie, aber auch die regulatorische und die Grundlagenforschung.
Nico Sonnenschein und Leroy Elenschneider vom Fraunhofer ITEM werden sich am Programm dieses Kongresses mit einem Vortrag und einer Posterpräsentation beteiligen. Zum Vortrag von Nico Sonnenschein zum Thema »Apparent permeability coefficients of ciprofloxacin in human lung epithelial cells appropriately predict bioavailability after inhalation exposure« laden wir Sie herzlich ein – nachfolgend das (englischsprachige) Abstract dazu:
Inhaled application of antibiotics is often considered in patients with pulmonary infections in order to achieve higher drug concentrations at the site of infection and to minimize systemic side effects. For the development of inhalable drug formulations, it is necessary to understand the pulmonary uptake mechanisms and to estimate the extent of systemic absorption. This study aimed at the determination of apparent permeability coefficients (Papp) of the inhalable antibiotic ciprofloxacin hydrochloride monohydrate (CHM) in human lung barrier models and to utilize these coefficients as input parameters for a lung PBPK model. Two different cell models were used to account for different lung regions: The Calu-3 cell line is a well-established immortalized cell line producing features of differentiated small airway epithelial cells. Functionally immortalized human alveolar epithelial cells (CI-hAELVi), resembling alveolar type 1 cells were used as model for the alveolar region.
Papp values were determined for submerged cultures and under air-liquid interface (ALI) exposure conditions. In both cases, the cells were cultured on permeable membrane inserts. For the submerged exposure, the antibiotic CHM was dissolved and added into the apical medium prepared for exposure. The cells exposed under ALI conditions were exposed to CHM aerosol generated using the PreciseInhale® device. For efficient and precise aerosol exposures, the P.R.I.T.® ExpoCube® was used. During the ALI exposure there was no liquid on the cells except for the lining fluid produced by the cells themselves.
After exposure the samples of the individual experiments were analyzed by LC-MS/MS and the Papp values determined. The cells under submerged conditions showed Papp values of 6.34*10‑7 cm/sec for AT‑1 cells and 7.24*10-7 cm/sec for Calu-3 cells. If the same thickness is assumed for the lining fluid layer for Calu-3 and AT-1 cells (2 µm) the resulting Papp coefficients of 1.99*10-8 cm/sec (AT-1) and 1.09*10-8 cm/sec (Calu-3) for the experiments under ALI conditions are nearly identical.
The Papp values obtained from in vitro transport experiments were used as input parameters for the physiologically based pharmacokinetic model (PBPK model) to simulate the absorption and distribution processes in the human body. The results obtained from the simulation were finally compared to human literature data. Blood level concentrations of Ciprofloxacin calculated by the model, using Papp coefficients from ALI exposure, showed the same concentration-time course and concentration range as measured in human patients. These findings suggest that a combined approach utilizing in vitro data and in silico modeling is able to predict the bioavailable dose after inhalation exposure in humans.
The authors acknowledge the excellent technical assistance of Martin Engelke, Antje Oertel, Andreas Hiemisch, Sabrina Meine and Susanne Gerling.