More from less: LC-MS/MS an Enabling Technology to Maximize Bioanalytical Data Collection from Small Sample Volumes
In this webinar, Dr Stuart Best, Deputy Director, Drug Metabolism and Pharmacokinetics (DMPK), Sygnature Ltd, will provide an overview of analytical approaches in Discovery Bioanalysis CNS measurement, to deliver more information from lower sample volume and align with the 3R principles.
Drug discovery programs that target the Central Nervous System require bioanalytical measurement of test compounds and neurotransmitter concentrations to establish a pharmacokinetic-pharmacodynamic (PK-PD) relationship. Bioanalytical assessment of unbound compounds in blood, brain tissue, and cerebrospinal fluid describes its distribution for the systemic circulation into the CNS. The inherently high sensitivity and specificity of LC-Triple Quadrupole Mass Spectrometry enables low level detection in small sample volumes, allowing serial sampling from single animals, reducing animal use and inter-animal variability, supporting the 3Rs principles (replacement, reduction, refinement)
The bioanalysis of neurotransmitters such acetylcholine and monoamines, is challenging due to low molecular weight, high polarity, instability, and low endogenous concentrations. At Sygnature, the in vivo Pharmacology team employ microdialysis to permit assessment of neurotransmitter changes in specific brain regions. The low endogenous concentrations in brain regions and collection through dialysis probe into artificial CSF lowers further quantitation limits for neurotransmitter detection and lead to the requirements for highly sensitive and specific analytical approaches.
This presentation will describe the above approached to CNS measurement and how LC-Triple Quadrupole Mass Spectrometry enables Sygnature scientists to align to the 3R principles and maximize data output from small samples and relate test compound concentrations to neurotransmitter changes. Truly, achieving on the concept of ‘More from Less’ Stuart will also present further refinement models for assessing test compound impact on acetylcholine and enabling more physiologically relevant measurements.
Key Learning Objectives:
- Understand the challenges as CNS measurements of test compounds and neurotransmitter concentrations to establish PK-PD relationships
- Explore the complexities of neurotransmitter bioanalysis in discovery DMPK due to low concentrations and instability
- Learn the roles of LC-Triple Quadrupole Mass Spectrometry enabling sensitive detection in small samples and alignment to the 3Rs (replacement, reduction, refinement) principles
Presenter: Dr Stuart Best (Deputy Director, DMPK, Sygnature Ltd)
Dr Best's expertise spans regulated and discovery bioanalysis and discovery DMPK, from supporting DMPK screening (solubility, log D, metabolic stability, permeability, plasma protein binding, etc) through in vivo assessment of compounds to more detailed profiling to support candidate nomination and human dose prediction, including the assessment of potential risk from drug-drug interactions.
During his time in the industry Dr Best has expanded the utilisation of mass spectrometry (specifically triple quadrupole LC-MS/MS) to help solve drug discovery project challenges with a strong focus on maximizing data capture from in vivo samples, refining experimental designs to permit better PD endpoints and expanding LC-MS/MS support for biological screening assays, where a mass spectrometry end-point is required, for the measurement of more challenging endogenous analytes.
