Pharmacokinetic and Pharmacodynamic Assessments of the Ivermectin and Levamisole Combination to Control Resistant Nematodes in Cattle

Combination of antiparasitic drugs with different mechanisms of action has been suggested as an effective strategy to delay the development of parasite resistance. Upon the need to understand the pharmacological basis of drug combinations, the current study evaluated the potential pharmacokinetic (PK) interactions and the clinical efficacy (pharmacodynamic response) occurring after the subcutaneous administration of ivermectin (IVM) and levamisole (LEV) given both separately and co-administered to parasitized calves on three commercial farms (A, B and C). Sixty (60) male calves naturally infected with gastrointestinal nematodes were randomly allocated into three groups (n= 15): IVM: treated with IVM by subcutaneous injection (0.2 mg/kg); LEV: treated subcutaneously with LEV (8 mg/kg); IVM+LEV: simultaneously treated with IVM and LEV (2 subcutaneous injections at the same dose rates). Seven (7) animals from each treated group (farm C) were randomly selected to perform the PK study. Drug concentrations were measured by HPLC. The therapeutic response (efficacy) was determined at 14 days after treatment by the fecal eggs reduction test (FECRT). The mean IVM area under the concentration vs time curve (AUC) obtained after administration of IVM alone (274 ng.d/mL) was similar to that obtained when IVM was co-administered with LEV (295 ng.d/mL). Likewise, mean LEV AUC values were similar after LEV administration alone (8.90 µg.h/mL) or combined with IVM (9.11 µg.h/mL). No adverse PK interactions were observed after the combined treatment, with similar PK parameters (P>0.05) obtained between the single-drug and the combination-based strategies. On farm A, the overall therapeutic responses (clinical efficacy) were 38% (IVM), 99% (LEV) and 100% (IVM+LEV). While the gastrointestinal nematode species Cooperia spp. and Haemonchus spp. survived the IVM treatment, Haemonchus spp. survived the LEV treatment. Similarly, total efficacies were 42% (IVM), 99% (LEV) and 100% (IVM+LEV) on farm B, and 54% (IVM), 99% (LEV) and 100% (IVM+LEV) on farm C. On those farms, IVM was ineffective against Cooperia spp. and/or Haemonchus spp., while LEV failed to control Ostertagia spp. Remarkably, the combination of both molecules was the only treatment that achieved 100% efficacy against all nematode genera (Cooperia, Ostertagia, Haemonchus and Oesophagostomum spp.). Based on the described PK-pharmacodynamic (PK-PD) assessment, the IVM+LEV combination appears to be a promising pharmacological option for controlling resistant gastrointestinal nematodes in cattle, with the additional potential to delay the progression of nematode anthelmintic resistance. Overall, the work described here contributes with sound and original pharmacology data useful to optimize parasite control in livestock. This drug combination strategy may enhance treatment efficacy while promoting more sustainable parasite management practices in cattle production systems.