Monepantel-based anthelmintic combinations to optimize parasite control in cattle

Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity. In this context, new chemical classes with novel mechanisms of action are required to defeat the threat of resistance but, despite the urgent need for innovation, development of novel anthelmintics has been slow (Nixon et al., 2020). Due to great difficulties associated with developing new anthelmintic compounds, improvement in the use of existing ones has been a high priority for research in the parasitology field. Therefore, the use of available pharmacology-based information is critical to design successful future approaches for parasite control in the current drug resistance scenario (Lanusse et al., 2018, Gilleard et al., 2021).

Monepantel (MNP), an amino-acetonitrile derivative (AAD), is one of the latest developed anthelmintics with a novel mode of action. Parasitic nematodes with reduced sensitivity to MNP have led to the identification of MPTL-1, a nematode-specific ligand-gated ion-channel subunit, as a potential drug target (Baur et al., 2015). Binding to this receptor results in a constant uncontrolled flux of ions and finally in a depolarization of muscle cells leading to nematode paralysis (Epe and Kaminsky, 2013). Its distinctive mechanism of action supports the high efficacy of MNP against nematodes exhibiting resistance to other anthelmintic classes (Baker et al., 2012). The commercial product, containing 25 mg/mL of MNP as the active ingredient, was introduced in New Zealand in 2009 and labelled for oral administration in sheep (Kaminsky et al., 2008, Hosking et al., 2010a). Some years later MNP was also introduced in a limited number of countries as an oral formulation for use in cattle (King et al., 2015. Zolvix® Plus Cattle – Efficacy against gastro-intestinal nematodes infecting cattle, in: 25th Conference of the World Association for the Advancement of Veterinary Parasitology WAAVP. Liverpool, United Kingdom, p. 263). The pharmacokinetic (PK) and pharmacodynamic (PD) performance of MNP, measured in terms of plasma disposition and anthelmintic efficacy in beef cattle, were recently reported by Canton et al. (2021). This study demonstrated the high efficacy of MNP against gastrointestinal (GI) nematodes resistant to IVM and ricobendazole (RBZ). However, low efficacy of MNP against Oesophagostomum spp. (efficacies ranging from 22 to 74%) was observed.

The lack of efficacy of MNP against Oesophagostomum spp. and reports of resistance to MNP in sheep (Scott et al., 2013, Mederos et al., 2014, Cintra et al., 2016, Hamer et al., 2018, Illanes et al., 2018) highlight the need to learn from use of this anthelmintic on sheep farms. Understanding the factors that encouraged development of resistance in these cases, such as frequent and solitary single drug treatments, is crucial to prolonging the useful life of MNP in cattle under field conditions. In this context, one strategy to improve the utilization of different anthelmintics into rational control programs is to administer them in combination (Bartram et al., 2012). Nematodicidal drug combinations have been validated as potential means of control by delaying the emergence of resistance and controlling parasite populations with existing resistance (Geary et al., 2012). In fact, considerable advantages in slowing the development of resistance to a new drug class are likely to be gained by releasing it in combination with one or more of the older anthelmintic classes, especially where efficacy of the older active ingredient remains high (Leathwick, 2012).

In this context, the present work was aimed at investigating potential drug-drug interactions and anthelmintic efficacy of MNP given alone or co-administered with either the macrocyclic lactone (ML) abamectin (ABM) or the benzimidazoles (BZ) albendazole (ABZ and its active metabolite RBZ), to calves naturally infected with resistant GI nematodes on two commercial cattle farms. In a context where available information on drug combinations in bovine livestock is rather limited, it is necessary to determine potential PK/PD interactions when two anthelmintic drugs are administered simultaneously under natural field conditions. Therefore, an integrated pharmaco-parasitological study for MNP-based drug combinations in cattle is described in the current work, which is critical to assess its use in scenarios of widespread anthelmintic resistance.

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