Contributions of Possible Storage Depots to the Pharmacokinetics of Inhaled Drugs. A. R. Moore, Battelle Memorial Institute
Preclinical safety and efficacy testing of inhaled pharmaceuticals normally involves animals inhaling an aerosol for at least several minutes whereas in the clinic often a single oral inhalation comprises the entire dose. The pharmacokinetics in animals can be described by a multiple dose model – each inhalation being a dose. A single dose model applies to humans taking a single inhalation. For the single dose model, virtually the entire lung Cmax comes from the aerosol exposure; in contrast, for prolonged exposures in animals the bloodside contribution can be important. For the same total dose, the lung Cmax in animals decreases as the exposure time increases and, when the Cmax may be critical for toxic or efficacious effects, the results from animal exposures of extended duration may have little predictive value for the clinic. Lung AUCs, on the other hand, depend only on the rate of absorption from the lung and pulmonary metabolism but not duration of exposure. Bloodside contribution to lung AUCs may be important if the absorption rate from the lung is fast relative to blood clearance and the drug partitions readily into the lung. These simple models, while having general applicability, describe only the pharmacokinetics of the bulk of the inhalant: a fraction may behave quite differently and be the only important contributor to effects. This may be the case for the candidate chemopreventive drug, isotretinoin, as the bulk of this prodrug apparently leaves the lung rapidly, yet carcinogenesis is repressed for at least four days post dosing. Moreover, although bloodside contributions to lung dose was, at first analysis, a major contributor to lung Cmax and AUC during pilot efficacy studies, oral studies that failed to provide efficacy suggest that extensive binding to blood proteins reduces the isotretinoin available for diffusion to the lung, leaving the airside isotretinoin as the only important contributor to lung dose and, hence, efficacy.
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