Considerations for toxicology studies of respiratory drug products.

The standard approaches for the preclinical development of chronically administered drugs also apply to most respiratory drugs. Modifications from the standard preclinical development plan, however, may be necessary if the drug is administered intranasally or by inhalation. Administration by these routes may result in airway toxicity and the intended patient population is often particularly susceptible. Current and former representatives of the Division of Pulmonary Drug Products (CDER, U.S. FDA) present this article to describe general principles of preclinical development for respiratory drug indications. The article addresses drugs intended for administration by the intranasal or inhalation routes. The article describes the types of studies recommended, considers the initial human dose, and discusses dose-escalation strategies in clinical trials. Other areas of special concern with intranasal or inhalation administration include immunotoxicity, reproductive toxicity, types of dosing apparatus, excipients and extractables, and formulation changes. The approaches described in this article are intended as general information and should be adapted to the scientific considerations and circumstances of a particular drug under development.

Nephrotoxicity and uptake of 1-benzyl quinolinium in precision-cut rabbit renal cortical slices.

Nephrotoxicity studies have not always meshed toxicity with transport and uptake, although the two are interdependent. To begin to address this issue, a series of model organic cations (quaternary amines) was examined which revealed differences in toxicity that were not explained by slight structural variations. Thus, a single model organic cation, 1-benzyl quinolinium (BQ), was used to assess organic cations in rabbit renal cortical slices. Histopathological evaluation revealed that BQ produced site-specific injury in the S(3) region of the proximal tubule. Biochemical assays (K(+), qO(2) and ATP) revealed dose- and time-dependent decreases of BQ-exposed slices over 2-12 hr. Cation transport (uptake of tetraethylammonium) was decreased by BQ at sub-toxic doses within 2 hr, although anion transport (uptake of p-aminohippurate) was not affected. Understanding the toxicity and transport of model cations such as BQ will help to identify the mechanisms associated with organic cation nephrotoxicity as well as to facilitate the use of transport parameters to prevent toxicity or prolong drug action of cations.