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WG3 - Pharmacokinetics and efficiency of AHs PDF Print

Leader: Marian Varady
Deputy: Elias Papadopoulos

A better knowledge on the specific pharmacokinetic profiles of antiparasitic drugs  in goats will lead to: i) a more efficient use of the registered chemical drugs; ii) a reduction in drug residues in food animal products; iii) a delay in the  development and spread of  resistance to chemical  drugs in parasite populations.  This will provide basic information to government or supranational agencies to implement the use of non-registered drug in the so-called orphan species, according to the rules of the European Medicinal Agency. Within this WG, 4 scientific tasks have been identified.

Task 3.1: Pharmacokinetics/ Efficacy of antiparasitic drugs in goats
It is hypothesised that the high prevalence of AH-resistant nematodes in goats is certainly due to the extensive off-label use of these at a standard ovine dosage, corresponding to a drug under-dosage. This example illustrates the importance of specific studies to gain information on drug pharmacokinetics in goat.
The therapeutic efficacy of antiparasitic drug relates to the bioavailability which depends upon the formulation of the dosage and the route of administration. The pharmacokinetic approach provides an efficient and accurate tool to ascertain the presence of a drug in the organism at a concentration and during a time-period compatible with optimal efficacy. Such increasing knowledge on the pharmacokinetic and metabolism patterns of drugs will allow to propose novel strategies to make more efficient the treatments in goats.
The current antiparasitic chemotherapy could be sustained by improving the pharmacokinetic performance of the drugs. Another way to improve the use of drug is to explore the drug-drug interactions. The Action will evaluate the influence of association of efflux inhibitors with antiparasitic drugs on their pharmacokinetics and their efficacy in goats. By inhibiting the drug efflux or metabolism, such approach will end at increasing the active compound into the host and the parasite organisms, making possible to reduce the amount of active compound given to animal. Moreover, because similar mechanisms participate to limit the entrance of drugs in host and in parasite, such associations can also help to reverse the resistance in parasites.

Task  3.2: Differences in resistance to antiparasitic treatments in goat production: What ?Why ?
Numerous factors are known to exert a likely influence on the emergence of resistant populations of GI nematodes to anthelmintics: the number of treatments given per year, the repeated and sometimes, exclusive use of certain drugs for many years (mainly due to the safety in use, the number of marketed drugs available in the same class and  the absence of a withholding period for milk or meat), the  under-dosing as most of the AH drugs need specific (=higher) dose rate for goats compared to the other ruminants, the size of the population of free living helminth stages on pastures at the time of treatment (called in refugia) determining  the rate of selection of resistance.
There is a need to analyse the available data and possibly to complete with AH resistance surveys with standard protocols, on a random basis. This will allow to have an accurate overview of AH resistance prevalences for the main drug families (benzimidazoles and probenzimidazoles, pyrantel-levamisole, macrocyclic lactones, narrow-spectrum drugs-e.g. closantel-) in different situations and to identify the main risk factors. These situations include GIN epidemiology (dominant species of nematodes, seasonal fluctuations, housing period, winter or summer periods of time, common and/or alternate grazing),the evaluation of  anthelmintic pressure and more largely of AH use (dose rates, alternation, frequency), grazing and breed management (intensive vs extensive breeding, meat vs dairy goats).
Information is particularly lacking for other drugs than benzimidazoles. Also, the question of worm populations expressing resistance to several drugs need to be addressed. Last, although resistance to antiparasitic drugs is highly prevalent in GINs, the phenomenon can also concern other classes of parasites and of chemical compounds (e.g. flukes)

Task 3.3: Sustainable use of antiparasitic drugs in goats
The resistance to AHs in nematodes has a strong genetic basis and results from a progressive selection process on worm population. Among the main factors involved in its development, the frequency of treatment and the size of worm population in refugia (not exposed to the drug) are considered as key factors of the selection pressure. Thus, the objectives are to reduce the selection pressure in order to prevent or more likely to slow down the emergence of AH resistance in goat flocks. Nowadays there is a consensus view that it is important to leave a proportion of the GIN population unexposed to treatment. This can be theoretically achieved through a reduction in AH treatment frequency and/or the implementation of targeted selective treatment (TST) towards those individual animals which are most likely to benefit from treatment in order to maintain anthelmintic susceptibility. This last option depends on relevant indicators that could be based either on clinical signs or on production considerations. Some of them (age, milk potential for dairy goats) have been tested successfully in some epidemiological or management systems but need to be evaluated more largely. In addition, others criteria (clinical, body condition, milk production, farmers judgement) to implement such targeted treatments request evaluation.

Task 3.4: Commercial use and registration:  
Meetings will be held to bring together scientists, authorities and pharmaceutical companies to discuss about regulatory issues on the use of drugs in goats and on the possible harmonisation of rules at the European level.

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