Expertise and capabilities
The rational design of new drug candidates relies on optimising many factors including potency and selectivity, synthetic tractability, safety, and pharmacokinetic properties to ensure safe and efficacious exposure profiles and convenient dosing regimens.
This iterative optimisation process focuses on the critical interplay between chemical structure, biological activity, and biodistribution properties to identify and progress drug candidates that are well-positioned for further development.
The CDCO aims to fill a critical gap in drug discovery by providing translational expertise on absorption, distribution, metabolism and excretion (ADME) and pharmacokinetic (PK) properties. Identifying ADME and PK liabilities during drug discovery is essential to guide appropriate structural modifications and identify strategies to mitigate risks during development. The CDCO’s involvement in drug discovery and development projects spans the period of “hit-to-lead” identification through to selection of a preclinical drug candidate.
We use a range of in silico, in vitro and in vivo methods to characterise the critical parameters needed to inform drug candidate optimisation and progression.
Physicochemical profiling
The physicochemical properties of drug candidates, including solubility, partitioning, ionisation and stability, underpin all aspects of drug formulation, delivery and disposition. Poor physicochemical properties can contribute to low bioavailability and unfavourable distribution properties.
Metabolism and Metabolite ID
Rapid metabolism is a major limiting feature of many drug candidates and can lead to low oral bioavailability, a short half-life or the production of potentially toxic metabolites. Understanding metabolic liabilities and pathways provides a rationale for structural modifications to reduce associated risks.
Permeability
Permeability across biological membranes is a key factor in the absorption and distribution of drugs. Poor permeability, which can arise due to a number of structural features as well as membrane-based efflux mechanisms, can lead to poor absorption or poor distribution throughout the body.
Pharmacokinetics
Pharmacokinetic properties dictate the route and frequency of administration, how extensively a drug is distributed throughout the body and how long efficacious concentrations are maintained. Adequate exposure at the site of action is essential to achieve maximum therapeutic efficacy.
Bioanalysis
The CDCO utilises time-of-flight and triple quadrupole LCMS instrumentation for rapid, specific and quantitative analysis of drug candidates and their metabolites in biological samples.
Binding and partitioning
An understanding of the extent to which a drug partitions into red blood cells and binds to proteins in plasma, tissues and in vitro assay media, allows for potentially improved in vitro - in vivo correlations of biological activity.