Preclinical Development of Orally Inhaled Drugs (OIDs)—Are Animal Models Predictive or Shall We Move Towards In Vitro Non-Animal Models?

Abstract

Respiratory diseases constitute a huge burden in our society, and the global respiratory drug market currently grows at an annual rate between 4% and 6%. Inhalation is the preferred administration method for treating respiratory diseases, as it: (i) delivers the drug directly at the site of action, resulting in a rapid onset; (ii) is painless, thus improving patients’ compliance; and (iii) avoids first-pass metabolism reducing systemic side effects. Inhalation occurs through the mouth, with the drug generally exerting its therapeutic action in the lungs. In the most recent years, orally inhaled drugs (OIDs) have found application also in the treatment of systemic diseases. OIDs development, however, currently suffers of an overall attrition rate of around 70%, meaning that seven out of 10 new drug candidates fail to reach the clinic. Our commentary focuses on the reasons behind the poor OIDs translation into clinical products for the treatment of respiratory and systemic diseases, with particular emphasis on the parameters affecting the predictive value of animal preclinical tests. We then review the current advances in overcoming the limitation of animal animal-based studies through the development and adoption of in vitro, cell-based new approach methodologies (NAMs).

A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms

“…In this context, one very important aspect is the widely acknowledged lack of reliable and predictive preclinical rodent models for inhaled therapies in general and chronic PA lung infections in particular. [ 34,35 ] This prompts researchers to make use of surrogate in vivo models or even consider moving toward solely non‐animal models. These aspects are currently being explored by us in order to propel the project further through the translational pipeline and will be reported on in future studies.…”

A Pathway From Porous Particle Technology Toward Tailoring Aerogels for Pulmonary Drug Administration

“…The inhalation therapy can also provide local treatments with higher efficacy and reduce side effects compared to systemic administration, by targeting directly the desired region and by increasing the drug concentration in the lungs ( Borghardt et al, 2018 ). The current annual rate of the global respiratory drugs markets is estimated at 4–6% with prospects of increase in the short-mid term ( Movia and Prina-Mello, 2020 ). The increasing interest in pulmonary drug delivery can be evaluated by the evolution of the number of publications on this topic, particularly in the recent years ( Figure 1 ).…”

“…Current challenges in the development of orally inhaled drugs are targeted to face the high overall attrition rate (70%) ( Movia and Prina-Mello, 2020 ). The complexity of lungs renders lung deposition as a critical factor in pulmonary administration determining the drug efficiency, which is generally associated with the volume of lungs, clinical status and breath patterns of patients, physicochemical properties of inhaled particles and design of inhalation devices ( Borghardt et al, 2018 ; Lavorini et al, 2019 ).…”

Are Animal Models Needed to Discover, Develop and Test Pharmaceutical Drugs for Humans in the 21st Century?

“…Human-relevant approaches are of interest to Dania Movia and Adriele Prina-Mello, who explore them in the context of orally inhaled drugs (OIDs) which are used to treat respiratory and other diseases [ 5 ]. Movia and Prina-Mello suggest that while the limitations of existing preclinical animal and in vitro models contribute to poor clinical translation in the field of OIDs, cell-based NAMs such as Air-Liquid Interface cell cultures, lung organoids and lungs-on-a-chip show exciting potential.…”

“…On the other hand, the “promote NAMs” movement is not without its problems. As Movia and Prina-Mello point out in this issue, many in vitro assays use transformed cell lines that may differ from their primary counterpart in terms of gene and protein expression [ 5 ]. Furthermore, in vitro studies are vulnerable to many of the same problems of experimental design as animal studies [ 16 ], and there is a need for greater standardization in cell culture (e.g., cell media, cell types, culture conditions, protocols used) in order to increase reproducibility [ 17 ].…”