Non-clinical dose formulation considerations
Designing appropriate non-clinical safety studies requires thoughtful, and sometimes experimental, consideration of the delivery methodology for the therapeutic. The choice of formulation affects drug release and absorption and has a direct impact on the pharmacokinetic profile and associated response of the model system. The formulation should be compatible with the study design, species, and test article.
During the discovery phase, the formulation needs to only sufficiently deliver the therapeutic to support proof-of-concept and lead target identification studies. The robustness of these formulations with respect to accuracy, homogeneity, repeatability and stability, is not typically considered until regulated safety data is being generated. For regulated preclinical work, formulations need to perform reliably and consistently while maximising exposure in the animal model to the therapeutic. To demonstrate that the formulations are robust, accurate analytical methods need to be developed and validated in accordance with regulatory expectations. Reference is usually made to the AAPS whitepaper1 for guidance on the typical analytical activities required to support GLP toxicology studies.
In generating investigational new drug (IND)-enabling data, three different formulations are commonly required for small molecules: one for the general toxicology safety evaluation studies; one used in the in vitro genetic toxicology assays (GeneTox); and one for use in the human ether-a-go-go (hERG) assay. The GeneTox formulation typically consists of a neat solvent, most commonly DMSO or water, and needs to span a wide range of concentrations (typically 0.001 to 100mg/mL). The hERG assay requires the formulation buffer to sustain the integrity and biological activity of the hERG patch clamp and is typically limited to physiological salt solutions that may contain low levels of organic solvent. The GeneTox and hERG formulations often require time to establish solubility limits and compatibility effects to ensure proper exposure. Such formulations fit a specific need and options are limited in the vehicle composition.
The analytical methodology for each formulation requires validation, and the stability of each formulation needs to be established. As a minimum, stability data must cover the duration between formulation preparation and time of dosing. Additional stability data is desirable to allow larger batch preparations, which leads to…