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Inhalation April 2024 39 using the "Alexander equation" [3]. Target doses can be achieved by adjusting the aerosol concen- tration and duration of admin- istration but there are limits for each based on practical and ethical considerations. For lung delivery, a 10-fold or 4-6-fold safety margin (above the clini- cal dose) is required for rodent and non-rodent species, respec- tively, and a 1-2-fold margin is required for achieved systemic exposure. ere is inconsistency in approach between regulatory agencies for safety margin calcu- lations for locally targeted expo- sure, with the US Food and Drug Administration (FDA) being the most cautious. In terms of trans- lation to the clinic, the dose which causes no adverse effects (i.e., the no observable adverse effect level or NOAEL) in Good Laboratory Practice toxicology studies, together with applica- tion of the safety margin, are what determines the Maximum Recommended Starting Dose for First-In-Human trials. Unlike safety studies that use healthy animals, efficacy studies often require a disease model in which to demonstrate therapeutic effects. Well-established respira- tory disease models include: • acute pneumonia (infection model), • neutrophilia (lipopolysaccha- ride model for adult respiratory distress syndrome, cystic fibro- sis and chronic obstructive pul- monary disease), • fibrosis (bleomycin model for idiopathic pulmonary fibrosis), • asthma (ovalbumin model using the Norway brown rat). Two examples were discussed in more detail: • Pn e u m o n i a — Ps e u d o m o n a s aeruginosa is a major cause of ventilator-acquired pneumonia and a risk factor for adult respi- ratory distress syndrome. Rats were administered a clinical strain of Pseudomonas aerugi- nosa by oropharyngeal aspira- ticle size distribution is key for calculating dose and determining the exposure achieved. ere are a variety of ways to expose the species commonly used in inhalation safety studies to aero- sol atmospheres. For drug devel- opment studies, administration is typically by nose-only cones or masks for rodents, dogs, minipigs and non-human primates. Train- ing and habituation of the animals to the experimental set-up is piv- otal from both ethical and scien- tific perspectives. Inhalation safety study designs and preclinical disease models Paul Smith (Charles River) explained the regulatory toxicol- ogy requirements that apply to inhaled medicines. Toxicology safety study designs are largely driven by ICH M3 (R2) [1] or S6 (R1) [2]. Non-clinical studies for pharmaceuticals are designed such that the duration varies according to the planned duration of stud- ies in the clinical development phases. In addition to the usual inhalation toxicology outcomes (e.g., clinical signs, body weight, food consumption, toxicokinetics, lung weight and histology), addi- tional endpoints may be required for inhaled biologics. It is also use- ful to incorporate safety pharma- cology endpoints into inhalation toxicology studies, if possible, as this provides an opportunity to evaluate effects after repeated dos- ing using a clinically relevant route of exposure. Inhaled toxicology studies are usually more expensive com- pared to other routes of exposure and require more active pharma- ceutical ingredient (API), due to inevitable losses during aerosol generation and delivery. Regula- tory toxicology generally requires studies using a rodent and non-rodent species. Lung dose is calculated based on detailed char- acterization of tightly- controlled delivered test atmospheres (con- centration and particle size) ments meticulously to investigate the study question was empha- sized. Multiple endpoints can often be used that combine signs of epithelial health (e.g., histol- ogy, cell/barrier integrity, ciliary beat frequency or individual cell characteristics), indicators of stress (e.g., inflammatory cytokines) and mechanisms of toxicity (e.g. sig- naling pathways). Exposure mode and "dose" are key considerations for in vitro studies; for example, the amount and con- centration of drug or formulation (whether administered in solution or by aerosol) and how drug lev- els relate to exposure scenarios in vivo. Establishing in vitro/in vivo correlation is important to support translation from cell and tissue experiments into animal testing, and the use of a well- characterized test article is an essential factor through all development phases to ensure that preclinical outcomes translate into the clinic. Delivery of aerosols for inhalation toxicology An(Tony) Grasiewicz (LabCorp) addressed the delivery of test materials in different respirable forms, focusing on liquid drop- let and powder aerosols that are relevant to inhaled medicines development. e principle is to generate an atmosphere that is respirable for the species in the study and allow the animals to inhale it. While it is sometimes possible to use clinical devices, they are designed for humans and it is more common not to utilize them. Liquid formulations deliv- ered by nebulization are com- monly used in early development. For pressurized metered dose inhaler (pMDI) formulations, atmospheres can be produced by actuating multiple canisters simul- taneously and repeatedly. For powder formulations, aerosols can be generated using capsule-based or bulk powder systems. Char- acterization of the atmosphere in terms of both aerosol concentra- tion (mass per volume) and par-