Interpretation and prediction of inhaled drug particle accumulation in the lung and its associated toxicity.

The increasing use of poorly-soluble inhaled dry powder pharmaceuticals means that animal toxicology studies of these drugs frequently produce lung changes related to the physical presence of undissolved particulate material within the alveolar spaces. These changes are independent of any chemically- or pharmacologically-mediated toxicity and present a challenge to drug developers and regulators in that risk depends on the retained lung burden of undissolved drug material, rather than the delivered dose, systemic exposure or duration of dosing as traditionally used in risk assessment for inhaled compounds. The methodology presented uses basic pharmacokinetic principles to estimate lung particulate burdens achieved in rat inhalation toxicity studies for four inhaled compounds which have reached clinical evaluation. The estimated lung particulate burdens and associated histopathological findings were compared with published thresholds for similar effects caused by inert particulates such as titanium dioxide. Results of the analysis illustrate that regardless of the duration of the study, estimated lung burdens in excess of ∼1 mg drug per g lung were associated with adverse changes consistent with those described in the literature for inert insoluble particles. For all low solubility inhaled pharmaceuticals so far examined, the calculated steady-state retained lung burden of drug in humans is several orders of magnitude lower than that associated with adverse effects in human or animals.