Roadmap for development of therapeutics for helminths

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

• Integration between the pharmacodynamic (drug-receptor interaction) and pharmacokinetic (time course of changes on drug concentration) data is critical to predict and optimise anthelmintic activity. The response to the following questions should drive the pharmacology-based search for new molecules:
• Is it possible to predict drug efficacy (PD) based on PK data?
• Is drug activity (efficacy) directly dependent on drug concentration achieved at the site of parasite location?
• Are plasma/serum drug concentrations a good indicator to predict either drug concentration at the site of parasite location or amount of active drug accumulated within a target helminth?
• How do plasma/serum drug concentrations correlate with drug levels attained at different target sites (i.e. GI fluids, skin, lung, liver, etc.) for each drug type (i.e. benzimidazoles, macrocyclic lactones, etc.)?
• How could the PK changes (induced by host physiology, co-administered drugs, etc.) affect the anthelmintic therapeutic response?
• Which are the main routes of drug entry into target parasites (oral, transcuticular/tegumental)? This information in needed for each anthelmintic/chemical group at each target parasite.
• Are there are other reliable parameters (in addition to the number of collected parasites/number of eggs passed in faecal material) to evaluate drug effect against helminths? (i.e. tegumental/cuticular alterations, loss of motility, etc.)

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

• To determine drug concentration required to kill/remove parasites. This information is necessary for each anthelmintic/chemical group, in different target parasites and in the different animal species in which the drug is intended to be used.
• To develop analytical techniques to accurately quantify drugs and/or metabolites in different tissues/fluids, including parasite material.
• To identify a reliable parameter to estimate when a parasite has been irreversibly affected by an anthelmintic molecule.

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

• Design and execution of experiments in order to collect PK (in plasma and organic fluids/tissues) and efficacy data.
• Development of in vitro/ex vivo approaches in order to find reliable parameters (surrogates) to estimate when the drug has irreversibly affected a parasite.

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

The `minimum effective concentration´ for anthelmintic drugs needs to be determined (for different drugs/metabolites, in different fluids/tissues, different animal species and for different parasites). Basic and detailed PK data for some existing anthelmintic drugs and for novel ones is needed (in some animal species). The development of accurate PK/PD models for use with anthelmintic drugs is urgently required.

Existing knowledge including successes and failures

The available integrated pharmacokinetic/pharmacodynamic and clinical pharmaco-parasitology knowledge is useful to optimize the use and to preserve traditional/novel anthelmintic compounds. The available basic pharmaco-parasitological information for different traditional anthelmintics (in different animal species) is relevant to improvinganti-parasitic therapy.