A novel formulation of ketorolac tromethamine for intranasal administration: preclinical safety evaluation.

Ketorolac tromethamine is a potent analgesic and moderately effective anti-inflammatory drug approved for treatment of moderately severe acute pain as an intravenous/intramuscular injectable solution and an oral tablet. ROXRO PHARMA, Inc has developed an intranasal formulation, SPRIX, that delivers the drug with a similar pharmacokinetic profile to that obtained with intramuscular administration. Local tolerance and systemic toxicology studies were performed in rats and rabbits and showed that intranasal administration of SPRIX exhibits toxicity similar to that of other routes of administration and does not result in any adverse effects on the nasal passage and upper and lower respiratory system.

Direct dosing of preweaning rodents in toxicity testing and research: deliberations of an ILSI RSI Expert Working Group.

Laboratory animal studies designed to assess the effects of exposure of a test substance during postnatal development are commonly utilized in basic research and to evaluate potential hazard to children for chemical and pharmaceutical regulation. Direct dosing, defined here as the administration of a test substance directly to a preweaning mammal, has been identified as a useful tool that can be used in the conduct of such studies for regulatory purposes. The International Life Sciences Institute Risk Science Institute (ILSI RSI) convened an Expert Working Group to develop guidance on the design and implementation of direct dosing regulatory studies on preweaning mammals, which was published as an ILSI monograph in 2003 (Zoetis and Walls, Principles and Practices for Direct Dosing of Pre-Weaning Mammals in Toxicity Testing and Research, Washington, DC: ILSI Press, 2003). A summary of the Working Group conclusions regarding direct dosing studies with laboratory rodents are presented here, although the ILSI monograph also includes rabbits, canines, swine and nonhuman primates. Issues to be considered when designing the protocol include selection of the test species, the route of administration, dose levels, and the timing of dosing. Knowledge of the maturational status of the test species and information on critical windows of development are important in creating a valid study design. Most common routes of administration (e.g., oral, inhalation, injection) are possible with typical laboratory species; however, adjustments may be necessary due to practical considerations. Information on the pharmacokinetic profile in young animals versus adults and in the test species versus humans is very useful for determining dosing parameters. The conduct of the study and the interpretation of the data will be improved by an understanding of confounding factors as well as statistical and biological issues specific for postnatal studies. Ultimately, the success of the study will depend upon careful preparation, including thorough training of the technical staff.