Title : 5-Tiered (pre-) formulation approach to support toxicology studies
Abstract:
The Beerse developability groups provides physchem and formulation support to both discovery and toxicology teams within Janssen Belgium. In early discovery, it is essential to keep pace with the discovery teams and assure timely delivery of solubility results using Semi High Throughput screens. Besides generating and interpreting data it is essential to align with medicinal chemists and take into account the solid-state optimization of certain lead candidates. Once moving into LO (lead optimization) and LLO (Late Lead Optimization) it is important to support the numerous efficacy and pharmacokinetic studies, taking key deliverables of discovery into account. At this stage, optimization of bioavailability by increasing the absorption potential (if possible), is usually limited to conventional formulation platforms. All knowledge gained during the previous phases, guides the development of formulations used in tolerance studies. Purpose of the non-GLP tolerance studies is to:
• Determine exposures associated with chemical toxicities in relation to the anticipated clinical efficacious exposures
• Determine MTD and establish target organs of toxicities
• Assist in determining dose levels for GLP studies
• Successful outcome should be a suitable margin between the observed toxicity and the concentration required for efficacy
Formulation and dose should be selected to maximize exposure in toxicity studies, rather than to maximize the dose. Formulation volumes to be administered should be based on anatomical and physiological attributes of the test species and the properties of the formulation. Chemical & physical stability of the formulation are important criteria for suitability for use in toxicity studies and could limit the selection of vehicles available for determining the MFD. To facilitate & support these studies a formulation decision tree of 5 tiers was developed. Conventional aqueous solutions or suspensions are preferred, but when exposures need to be improved exploration of non-conventional systems will be explored.
Audience take away:
• How the introduction of a semi-HT Equilibrium screen allowed to assess pH dependent solubility as well as solubility in biorelevant media to support early MAD limitations.
• Specific tox findings of certain vehicles will be presented
• Guidelines apply to the assessment and selection of which vehicle(s) can be used for pre-clinical non-GLP and GLP toxicity studies as a function of overall compound developability
