Innovative preclinical models for pulmonary drug delivery research

ABSTRACT

Introduction: Pulmonary drug delivery is a complex field of research combining physics which drive aerosol transport and deposition and biology which underpins efficacy and toxicity of inhaled drugs. A myriad of preclinical methods, ranging from in-silico to in-vitro, ex–vivo and in-vivo, can be implemented.

Areas covered: The present review covers in-silico mathematical and computational fluid dynamics modelization of aerosol deposition, cascade impactor technology to estimated drug delivery and deposition, advanced in-vitro cell culture methods and associated aerosol exposure, lung-on-chip technology, ex–vivo modeling, in-vivo inhaled drug delivery, lung imaging, and longitudinal pharmacokinetic analysis.

Expert opinion: No single preclinical model can be advocated; all methods are fundamentally complementary and should be implemented based on benefits and drawbacks to answer specific scientific questions. The overall best scientific strategy depends, among others, on the product under investigations, inhalation device design, disease of interest, clinical patient population, previous knowledge. Preclinical testing is not to be separated from clinical evaluation, as small proof-of-concept clinical studies or conversely large-scale clinical big data may inform preclinical testing. The extend of expertise required for such translational research is unlikely to be found in one single laboratory calling for the setup of multinational large-scale research consortiums.

KEYWORDS:

• Nebulization
• aerosolization
• inhalation
• theoretical modeling
• cell culture techniques
• animal models

Article highlights

• All aspects of preclinical evaluation of pulmonary drug delivery, i.e. in-silico, in-vitro, ex–vivo and in-vivo methods have undergone important improvement and refinements.

• Hybrid multiscale mathematical modeling, improved cascade impactor technology, complex multicellular air–liquid interface cell cultures, and associated drug delivery devices, lung-on-chip bioengineering 3D models, reliable, and reproducible in-vivo inhaled drug delivery methods are among the most important recent innovations.

• The multidisciplinary expertise required to cover the whole spectrum of preclinical testing calls for setting up multi-national large-scale collaboration consortiums.

Acknowledgments

The authors sincerely thank Mark Nagel and Jason Suggett from Trudell Medical (London, Ontario, Canada) for sharing their expertise from the development of upper airway models. Otmar Schmid was partially funded by the German Federal Ministry of Education and Research (BMBF: FKZ 13XP5069A) and the Proof-of-Concept Initiative of the Helmholtz Association of German Research Centres and the Fraunhofer Gesellschaft (PoC-0033). Chantal Darquenne’s contribution was supported by the National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health under Award Number U01ES028669. Barbara Rothen-Rutishauser and Hana Barosova acknowledge the support of the Adolphe Merkle Foundation. The authors thank the ERA-NET EuroNanoMed III program (joint transnational call 2017 for “European innovative research & technological development projects in nanomedicine” program: Agence National pour La Recherche and German Federal Ministry of Education and Research: BMBF) supporting the INAT project that coordinates research efforts to optimize aerosol delivery in mice.

Declaration of interest

S Ehrmann has disclosed consultancies from Aerogen Ltd, La Diffusion Technique Française and Bayer Healthcare, research support from Aerogen Ltd, Fisher & Paykel healthcare, Hamilton medical, travel reimbursements from Aerogen Ltd and Fisher & Paykel. N HeuzéVourc’h is co-founder and scientific expert for Cynbiose Respiratory and receives consultancy fees from Argens, and research support from Sanofi, Aerogen Ltd and Signia Therapeutics. O Schmid has disclosed consultancies from AstraZeneca, Data Science (DSI), Bene-Arzneimittel, EMKA/Scireq, VITROCELL Systems. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the German Federal Ministry of Education and Research [BMBF: FKZ 13XP50691]; Proof-of-Concept Initiative of the Helmholtz Association of German Research Centres, the Fraunhofer Gesellschaft [PoC-0033]; National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health under Award Number [U01ES028669]; Adolphe Merkle Foundation, ERA-NET EuroNanoMed III (joint transnational call 2017 for ‘European innovative research & technological development projects in nanomedicine’ program: Agence National pour La Recherche and German Federal Ministry of Education and Research: BMBF) supporting the INAT project.