DM-MAP: drug and metabolite microsampling analytical platform for preclinical medicines development

Aims

This project aims to develop a drug and metabolite microsampling analytical platform (DM-MAP) that requires small blood volumes and therefore minimises the number of rodents used by allowing pharmacological and pharmacokinetic data to be obtained from the same animal.

Background

Discovery stage pharmacology and pharmacokinetic studies are used to assess whether a new compound should be developed further. Typically, because of the blood volumes required for analysis, two separate groups of animals are used; satellite animals for pharmacokinetic data such as drug and metabolite concentrations at different time points and other animals for study of pharmacological endpoints. A new analytical method that could easily and accurately obtain both pharmacokinetic and pharmacological data from small blood volumes taken from the same animal at multiple time points would substantially reduce the number of rodents that are required for these early stage studies by avoiding the use of satellite animals.

Research details and methods

This project is based on the use of solid phase microextraction, an emerging analytical technique using biocompatible, coated microfibres to adsorb compounds from complex biological sample matrices. The reduced sample volumes required will permit repeated blood sampling from an animal being studied for the pharmacological effect of a drug.   

Preclinical testing is used to demonstrate efficacy and to characterise risks during drug development. One problem to be overcome is the provision of quality data to support decision making when progressing a compound through development phases. Discovery stage pharmacology and pharmacokinetic (PK) studies are used to assess compound developability. In this studentship we propose developing a Drug and Metabolite Microsampling Analytical Platform (DM-MAP) to improve the quality of data obtained from discovery-stage study protocols. The project aims to provide a platform to the pharmaceutical research community to combine pre-clinical pharmacology and PK discovery studies by reducing the blood sample volumes required to be removed, for studies typically performed in rodents. The solution we propose is to use solid phase microextraction (SPME), an emerging analytical technique employing biocompatible, coated microfibers to adsorb compounds from complex biological sample matrices. Due to their size, microfibers appear suitable for insertion directly into organs or tissues (e.g. blood, dermis, liver) to detect the presence of drug or metabolites. Once validated, SPME microsampling will reduce sample volumes removed when determining drug concentration. Thereafter it will be feasible to perform a PK study for drug concentration in the same animal that is being studied for pharmacological effect. This will remove the need for 'satellite' treatment groups, i.e. animals administered compounds solely for concentration determination. In combination with analytical techniques (e.g. mass spectrometry), we will validate SPME to perform sensitive qualitative and quantitative analysis of drug and metabolite concentration directly within organ tissues and body fluids. The student undertaking this project will address the shortfall in information on tissue distribution of compounds, which can currently only be determined in animals at a single time point using terminal procedures.