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Clinical Significance of Animal Models for Inhaled Pharmaceuticals and Biopharmaceuticals

Pre-clinical studies are crucial when studying the effects potential inhaled pharmaceuticals and predicting their possible toxicological impacts prior to a clinical trial. Animals exhibiting human-like disease characteristics are important in disentangling the effect of these compounds within the whole system of a body and inclusion of important factors such as upper airway architecture, airway turbidity during breathing etc. are not replicable in organoid or in vitro studies. In the pre-clinical realm, systems such as the flexiVent (SCIREQ inc) can integrate with a hospital grade nebulizer (Aerogen Inc) to generate targeted inhaled drug delivery that is aligned with user controlled subject ventilation. Use of this tool can produce optimal outcomes for distribution and deposition of the aerosol in the airways of a given subject background and species. In addition to having the correct tools, knowing which model is available and most directly answers a scientific inquiry vs what may be locally available are important factors to consider when designing a study. To this end, excellent overviews of experimental models and their relevance in pharmacodynamics, pharmacokinetics, and toxicological studies of inhaled drugs, such as the recent paper by Secher et al. are critical.

Drug Loss With Inhaled Pharmaceuticals

Pharmacokinetics are the study of absorption, distribution, metabolism, excretion, and optimal dosing for drugs, including newly synthesized compounds. Only a small portion of an available solution generated by a nebulizer will reach the lung tissue, with the remaining fractions being lost in the aerosol device, spread in the environment, or deposited in the oro-nasopharynx and subsequently swallowed. In humans, factors including the aerosol particles’ size and drug formulation are known to impact deposition of inhaled drugs. In non-obligate nose-breathing species such as humans, monkeys, and dogs, a similar deposition of 1-5 μm particles is exhibited overall, while nasal obligate prey species such as rats demonstrate lower deposition levels (citation). As might be expected, nasal and tracheobronchial deposition is more pronounced in rats than in humans. The particle size for optimal aerosol deposition varies among species, with rats achieving maximal relative lung deposition with 1 μm particles, whereas 2-4 μm particles are more appropriate for human lungs (Wolff & Dorato, 1993).

Inhalation Toxicity Study Guidelines

Inhalation toxicity study guidelines during drug development are limited and those available are similar between inhaled and non-inhaled pharmaceuticals. Guidelines include: (1) animals should be small enough to facilitate handling, housing, and exposure to support reliable statistical analysis and (2) animals must be large enough to enable comprehensive measurement of the toxicity of the inhaled substance (Secher et al., 2020). Factors including strain, age, health status, and housing conditions of the animal model in use are consistent for inhalation vs non-inhalation drug testing however the test atmosphere and acclimatization periods for dosing are route specific and can impact toxicity evaluation. It is possible to direct compounds towards the animal’s breathing zone to decrease the necessary dose while still achieving adequate lung deposition. In such a way, experimental conditions can be modified to better replicating human inhalation. For rodents and other lagomorphs, this can be achieved using nose-only exposure systems such as the inExpose system, while non-rodent species such as dogs, sheep, and monkeys are typically exposed using helmets, face masks, or oro-pharyngeal tubes.

Asthma, COPD and Influenza Animal Models

For airway inflammation and bronchial hyperresponsiveness studies guinea pigs and ferrets are commonly used due to their ability to cough and to sneeze. In addition, the presence of M2-,M3-muscarinic and B2-adrenergic receptors within guinea pig lungs, similar to human lungs, lead to closer mimicry of bronchoconstriction induced by methacholine and acetylcholine as tested in clinical COPD and asthma studies (Canning, 2003). The main disadvantage of guinea pigs for such research applications is the lung axon reflex which is not observed in humans. This reflex occurs where increased sensitivity of airway nerves develops in response to dose challenges. The limited diversity of wild type or genetically modified strains, relative to mouse and rat models, also restricts use of these animal models for examinations into the molecular mechanisms of allergies or COPD. Ferrets are most frequently employed as an infectious model organism ex. influenza study, as they exhibit clinical symptoms including sneezing, fever, nasal discharge, and inflammation following infection. The transmission of influenza virus between ferrets recapitulates essential and natural process of influenza infection and their upper and lower respiratory tract is more similar to humans than other models, such as mice (Oh & Hurt, 2016).

Pneumonia and Cystic Fibrosis Animal Models

Pneumonia and cystic fibrosis are bacterial lung infections can be treated with inhaled antibiotics and such antibiotics are often tested on bacterial culture rather than in animal models when seeking to better understand their mechanism of action and resistance. However, the development and investigation of inhaled antibiotics such as a compound targeting P. aeruginosa found in cystic fibrosis respiratory infections, requires preclinical studies including animal models such as mice when moving from theory to actualized therapy in the clinic). A wide selection of surfactants to treat respiratory distress syndrome have likewise been tested and developed thanks to preclinical studies in premature rabbits and lambs (see Table 2 within Secher, et al. (2020) for examples.

In conclusion, many animal models are available for preclinical drug development, including for aerosolized drug compound candidates. Each model has advantages and disadvantages. While no single model will fully recapitulate human lungs physiology or disease phenotypes, such studies permit evaluation of important health outcomes and help to assure that conclusions more accurately indicate future clinical success.

References

  1. Canning. (2003). Modeling asthma and COPD in animals: a pointless exercise? Current Opinion in Pharmacology; 3(3): 244-250. DOI :10.1016/S1471-4892(03)00045-6.

  2. Oh & Hurt. (2016). Using the ferret as an animal model for investigating influenza antiviral effectiveness. Frontiers in Microbiology; 7(80). DOI: DOI: 10.3389/fmicb.2016.00080

  3. Secher, et al. (2020). Correlation and clinical relevance of animal models for inhaled pharmaceuticals and biopharmaceuticals. Advanced Drug Delivery Reviews, 167: 148-169. DOI: 10.1016/j.addr.2020.06.029

  4. Wolff & Dorato. (1993) Toxicologic Testing of Inhaled Pharmaceutical Aerosols, Critical Reviews in Toxicology; 23(4): 343-369. DOI: 10.3109/10408449309104076

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