Principal Investigator (PI)
University of Dundee
The Foundation is providing £254,812 in support.
Professor Roland Wolf
Dr. Kenny MacLeod
Aileen Ward
Cristina Merino
1. Murine P. falciparum and P. berghei infection models, P3 facilities used and related staff expertise.
2. Bioanalytical capabilities for analysis of samples from infection models and related staff expertise
3. Expertise in in silico modelling of drug PK and PD.
During project TC287, “Evaluation of P450 humanized mouse model (8HUM) as a tool to assess the impact of drug combinations on pharmacology”, we demonstrated that removal of species differences in compound metabolism through the application of this transgenic line improved the preclinical modelling of pharmacokinetics, humanisation of metabolite profile and prediction of drug-drug interaction (DDI). Moreover, our findings indicated that avoidance of mouse-specific metabolic liabilities through replacement of wild-type (WT) mice with 8HUM in existing models of M. tuberculosis, T. cruzi and L. donovani infection would allow progression of a greater proportion of compounds during lead optimization programmes. This finding has produced immediate impact within our kinetoplastid drug discovery portfolio.
Here, we propose to investigate whether a new immunocompromised line, 8HUM/Rag2-/-, can be integrated within the existing anti-malarial drug discovery and development workflow at the University of Dundee and GSK Tres Cantos. We will carry out basic characterisation of the line in comparison to 8HUM and will determine to what extent 8HUM/Rag2-/- can be engrafted with human erythrocytes and infected with P. falciparum, the most relevant translational model for human disease. If successful, we will determine the pharmacokinetics of approximately ten anti-malarial monotherapies and ten two-drug combinations (for which the victim is an anti-malarial and the perpetrator is used to treat either malaria, tuberculosis or HIV, and for which a clinical DDI has been reported) in 8HUM and/or 8HUM/Rag2-/-. Finally, we will test selected monotherapies and combinations in the 8HUM/Rag2-/- infection model, at clinically relevant levels of exposure, in order to relate PK and DDI to efficacy. Alternatively, if engraftment and infection of 8HUM/Rag2-/- is unsuccessful, we will validate P. berghei infection of 8HUM for all efficacy work.
In malaria, all new drugs entering Phase II trials are administered in combination with a partner drug of differing mode of action and comparable pharmacokinetics. Currently, such combinations are not trialled until clinical development, after the new compound has demonstrated clinical efficacy as a monotherapy. If successful, our methodology will illustrate how the efficacy of drug combination selection can be tested much earlier during preclinical development, and in the context of humanised metabolism, clinically relevant active metabolites, and potential for DDI. This will lead to design of clinical trials with a much greater chance of success.