Roadmap for development of therapeutics for helminths

What are we trying to achieve and why? What is the problem we are trying to solve?

• The rationale behind using drug combinations is based on the fact that individual worms may have a lower degree of resistance to a multiple component formulation (each chemical with different mode of action/resistance) compared to that observed when a single anthelmintic molecule is used. The resulting low number of surviving parasites with resistant genotypes would be diluted into the nematode population in refugia, and the resistant worms would take longer time to increase to the point of being predominant. The challenge will be to identify a combination between drugs (or between a synthetic drug and a phytochemical ingredient) resulting in a broad spectrum of very high activity against resistant helminth parasites. Response to the following questions should focus the research in this specific pharmacology-based field:
• Could anthelmintic combinations increase drug efficacy if AR is already present?
• Could anthelmintic combinations delay the development of resistance?
• Could the use of anthelmintic combinations be a sustainable control measure in field conditions?
• Are there associated risks to the use of anthelmintic combinations? Host toxicity? Tissue residues?
• Should anthelmintic combinations be used as fix preparations or as separate compounds concomitantly used?
• How can the favorable anthelmintic synergistic effects of drug combinations be optimised at the farm level?
• Which will be a rationale rotation scheme to extend the lifespan of those advantageous drug mixtures?
• What is the level of efficacy that should be targeted in a combination to maximize/optimize the ability to delay the development of resistance.

What are the scientific and technological challenges (knowledge gaps needing to be addressed)?

• Lack of plasma PK data for different anthelmintics administered alone or in combination in some animal species (i.e. goats, sheep).
• Lack of efficacy data for different anthelmintics administered alone or in combination in different animal species.
• Lack of plasma PK and efficacy data of anthelmintics administered alone or combined with different API (i.e. metabolic inhibitors, transporters modulators/substrates, etc.).
• Further understanding of underlying mechanisms behind anthelmintic resistance.
• Long-term field trials testing the strategy of using combinations to delay the development of AR

What approaches could/should be taken to address the research question?

• PK studies of different traditional/novel API with anthelmintic activity administered alone or in combination.
• Efficacy studies for different anthelmintics administered alone or in combination.
• Drug tissue residues depletion for molecules administered alone or in combination.
• ´Target´ species toxicity studies of different anthelmintics administered alone or in combination.
• Long-term studies investigating the benefits of combinations in delaying the development of AR

What else needs to be done before we can solve this need?

Development of novel anthelmintic molecules. Search of new APIs useful to be used in combination. This is a critical issue affecting all the Lead Summary 5C.

Existing knowledge including successes and failures

• Plasma PK data of different anthelmintics administered alone or in combination in different animal species is available.
• Efficacy data of different anthelmintics administered alone or in combination in different animal species is also available.
• We also have available data on plasma PK data for some anthelmintics administered alone or combined with different API available (i.e. benzimidazoles with metabolic inhibitors, endectocides with P-gp  modulators/substrates, etc.).