Symposium Summary

Abstract

Developing inhaled drugs requires knowledge of lung anatomy, cell biology, respiratory physiology, particle physics, and some plumbing. Although dose makes the poison, in the context of an inhaled drug, the "dose" is not easily defined. This lack of clarity around dose poses issues and challenges in the design of inhalation toxicology programs. To better understand dose, the influence of ventilation is discussed as are the perturbations in pulmonary function observed with inhalation exposure that can affect dose. Methods for determining inhaled drug deposition to arrive at an estimate of lung dose are examined. Equally important to understanding dose are the techniques used to deliver aerosols to animals. With a better understanding of dose and inhalation exposure, species-specific histopathologic lesions, both common background and toxicologically significant lesions, are reviewed. Finally, insight into how regulators synthesize and evaluate these complex findings to assess clinical safety risks is presented.

Pharmacokinetic Profile of Inhaled Submicron Particle Paclitaxel (NanoPac®) in a Rodent Model

“…Varying MMAD sizes results in different fractions of total aerosol to be deposited within the lung; FDA assumes 10% deposition fraction for rodents inhaling particles with MMAD 1–5 μm. 37,38 Previous analysis with Hospitak nebulizers assumed nebulization droplets to fall within this range for the Up-Mist nebulizer.…”

Novel Toxicology Program to Support the Development of Inhaled VentaProst

“…Overall, lung deposited dose rates of 0, 0, 60, 150, and 320 ng/kg/min were delivered after applying a 10% deposition factor to the delivered dose. 7 Mean mass median aerodynamic diameter (MMAD) values were 1.03, 1.27, and 1.38 mm for groups 3 to 5, respectively; corresponding geometric standard deviation (GSD) ranges were 1.66 to 1.85, 1.76 to 1.90, and 1.77 to 1.80, respectively. The mean MMAD value for the pH10.5 diluent was 1.34 mm; the GSD ranged from 1.28 to 2.70.…”

“…By convention, based on particle deposition data of different particle sizes in different species, 18 a deposition factor is applied to the delivered dose of 10% in rodents and 25% in nonrodents, to estimate the pulmonary deposited dose. 7 In the case of epoprostenol, as the half-life is so short and because surgeons are used to delivering it intravenously at a known rate, we have expressed the pulmonary deposited dose as a rate per minute for easy comparison to the clinical literature.…”

“…Rodent species can generally only tolerate nose-only inhalation for up to 4 to 6 h/ d, while most nonrodent species can only be oronasally exposed for up to 2 h/d. 7 Epoprostenol administration for up to 14 days in unanesthetized animals didn't seem to mimic the patient experience of up to 48 hours continuous inhalation exposure in anesthetized, intubated, and ventilated patients. Thus, these differences in physiological state, which affect both hemodynamic measurements and aerosol particle deposition, were not well modeled by the standard inhalation toxicology testing paradigm.…”

Use of precision cut lung slices as a translational model for the study of lung biology

“…With regards to safety of inhaled therapeutics, key functional aspects and damage are assessed using well-validated pathological readouts on standardized safety studies intended for safety pharmacology assessments [110]. However, less well-defined is the impact on adverse impact on the immune system in the lung, particularly in response to the targeting of anti-inflammatory pathways and immune cell function with inherent risk to host defense.…”