Drug Delivery to the Lungs, Volume 30, 2019 - Otmar Schmid

The Role of Aerosols in Preclinical Drug Development

Otmar Schmid12

1Comprehensive Pneumology Center Munich, Max-Lebsche-Platz 31 81377 Munich, Germany

2Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764 Neuherberg/Munich, Germany

Summary

In spite of the wide spread use of therapeutic aerosols for treatment of lung diseases, aerosols are virtually absent in preclinical lung research, where drugs are mainly pipetted into cell culture medium or instilled/aspired (not inhaled) into the lungs of animal models. This may have been largely due to a combination of the simplicity and apparent accuracy of non-aerosol based drug application as well as the lack of easy-to-use and yet efficient and dose-controlled technologies for delivery of therapeutic aerosols to preclinical models of the lung. In this talk I present recent advances in respiratory aerosol science filling this technological void and I will demonstrate that aerosol should play a more prominent role in preclinical drug development.

During the past decade a number of new technologies for aerosolized drug delivery in preclinical settings have been introduced. Focusing on commercially available devices the featured aerosol technologies include the ALICE-CLOUD technology for in vitro cell exposures (VITROCELL-CLOUD; VITROCELL Systems, Germany) and the flexiVent system for ventilator-assisted aerosol inhalation combined with lung function measurement in in vivo animal models (flexiVent FX; Scireq, Canada). Both systems are equipped with clinically relevant nebulizers (Aeroneb Lab/Pro; Aerogen; Ireland) providing dose rates and hence exposure times similar to clinical settings (a few minutes). Among the advantages of aerosols is the more physiologic pulmonary drug distribution in the lungs of mice after aerosol delivery as compared to intratracheal/intransal instillation. This is demonstrated by in vivo and ex vivo imaging utilizing propagation-based phase contrast X-ray imaging and light sheet fluorescence microscopy on non-dissected, optically cleared murine lungs (Yang et al., 2019; Gradl et al., 2019). In addition to drug distribution control over the tissue-/cell-delivered dose is essential for preclinical drug testing. Thus, the VITROCELL-CLOUD is equipped with a quartz crystal microbalance (QCM) for real-time dosimetry and the flexiVent system has been experimentally characterized for lung-delivered dose for a wide variety of ventilator settings and nebulizer types.

Respiratory aerosol technologies can improve the predictive power of preclinical studies for clinical outcome. This will be demonstrated for drug efficacy and physiologically-based pharmacokinetics (PBPK) testing with air-liquid in vitro cell models of the lung, which reveal that cell-delivered dose but not drug concentration in the medium is often governing drug efficacy (Lenz et al., 2014; Schmid et al. 2017). Moreover, the use of dose-controlled aerosol inhalation can improve animal models of lung disease. As an example, the capability of the flexiVent system to standardize bronchial challenge testing using aerosolized methacholine is pursued. Bronchial challenge testing is a key diagnostic tool for both preclinical and clinical testing of airway hyperresponsiveness in asthmatic subjects. Various dose measures ranging from the established methacholine concentration over the ERS (European Respiratory Society) recommended inhaled dose (Coates et al., 2017) to tissue-delivered dose are investigated for their biological relevance. Finally, in vitro/in vivo extrapolation (IVIVE) will greatly benefit from these new technologies as will be demonstrated for acute inflammation induced by inhaled biopersistent (nano-)particles, which has substantial implications for nanocarrier-based drug formulations.

In summary, these new respiratory aerosol technologies for in vitro and in vivo models of lung disease are expected to improve currently available animal models and pave the way for preclinical drug testing, which is more predictive for clinical outcome.

ERS technical standard on bronchial challenge testing using aerosolized methacholine (Coates et al., Eur. Respir. J., 49: 1601526, 2017).

Drug Delivery to the Lungs, Volume 30, 2019 - The Role of Aerosols in Preclinical Drug Development

Figure 1. Aerosol inhalation (left panel) using the flexivent system provides significantly more uniform deposition of drugs throughout murine lungs as compared to intratracheal instillation (left panel), which results in patchy deposition preferentially in the proximal region of the lung. This is revealed by light sheet fluorescence microscopy on non-dissected murine lungs after optically clearing the lung tissue (green: tissue; red: “drug” – here fluorescent nanoparticles) (Yang et al., 2019)