Discovery of new medicines in the early phases of drug development is driven by the expansion of new targets, target classes, and the development of innovative chemistry. Now more than ever, there is more need for the early testing of molecules with proper formulations in animal models for both pharmacology and disease modulation. The reliable and reproducible delivery of experimental compounds into animal models is a necessary step in the evaluation of compounds. The discovery development testing process can be broken down into distinct steps outlined below:
- Proof of concept/ Target validation: In this step, compounds of interest from functional screens are used to test a potential set of compounds that have acceptable properties to exert action, and the ability to modulate selected targets. These compounds typically have poor drugability properties and have undergone little medicinal chemistry efforts. In these studies, formulations that have high solubilizing properties are selected to be able to deliver large drug loads and have minimal tolerability issues in the short-term studies. These formulations are focused on using excipients and cosolvents that allow the rapid and reliable dissolution of small quantities of compounds without significant development time or compound synthesis scale-up. Typically, compounds are dosed intravenously or intraperitoneally to allow reproducible measurements of pharmacokinetics and target engagement. This is particularly important for novel targets as the pharmacological modulation in complex systems can be quite different than cell-based models. At Noble Life Sciences, we have developed a robust selection of discovery to allow the identification of an appropriate formulation with minimal use of compound and rapid turnaround.
- Pharmacology and tolerability evaluation: In this step, compounds are tested for the ability to be stably formulated, have appropriate pharmacokinetics and bioavailability, and the ability to dose at the level and frequency required to advance the disease model studies. In this step, formulations become increasingly complex and are optimized for stability in solution, exposure in animals, and single and repeated dose tolerability. Formulation components typically expand to testing not only excipients but also suspensions and nanosuspensions, pH and salt form adjustment, lipids, and solid dispersions. These techniques allow the identification of dose forms to successfully test long-term tolerability of the molecule and transition to successful testing of efficacy in animal models. More complex toxicity studies to measure serum chemistry, hematological and tissue pathology can be performed to identify any dose-limiting toxicities that are introduced from the compound or from the formulation.
- Disease model testing: At this point, the properties of the molecule and disease models will be used to scale up a formulation that will give confidence when entering the expensive and time-consuming studies to test the ability of the compound to modulate disease. Parameters such as target drug concentration in blood or tissue, frequency, and route of dosing, species used for disease models are used to select and test a lead formulation. This stage offers an opportunity to test alternate dose methods (subcutaneous, continuous infusion, food additive, etc.) that may be required for optimal testing. More complex tolerability testing in disease species can be performed to optimize
exposure.
Figure 1. Considerations for formulation development in early drug development:. This figure is reproduced from Zane et al., 2019 1
The successful progression of your molecule through these early stages of development gives the confidence to commit significant resources to the selection of a clinical lead and commitment to clinical formulation development, full-scale disease model testing, and IND enabling toxicology.
1P. Zane, H. Gieschen, E. Kersten, N. Mathias, C. Ollier, P. Johansson, A. Van den Bergh, S. Van Hemelryck, A. Reichel, A. Rotgeri, K. Schäfer, A. Müllertz, P. Langguth, In vivo models and decision trees for formulation development in early drug development: A review of current practices and recommendations for biopharmaceutical development, European Journal of Pharmaceutics and Biopharmaceutics, Volume 142, 2019, Pages 222-231, https://doi.org/10.1016/j.ejpb.2019.06.010.