Pharmacokinetic and pharmacodynamic assessments of the ivermectin and levamisole combination to control resistant nematodes in cattle

Abstract

Background/Objectives: Combination of antiparasitic drugs with different mechanismsof action has been suggested as an effective strategy to delay the development of parasiteresistance. Considering the need to understand the pharmacological basis of drug combinations, the current study evaluated the potential pharmacokinetic (PK) interactions and theclinical efficacy (pharmacodynamic response) occurring after the subcutaneous administration of ivermectin (IVM) and levamisole (LEV), administered either as single treatmentsor concurrently to different groups of parasitized calves on three commercial farms (A,B and C). Methods: Forty-five (45) male calves naturally infected with gastrointestinalnematodes were randomly allocated into three groups (n = 15): IVM, treated with IVMby subcutaneous injection (0.2 mg/kg); LEV, treated subcutaneously with LEV (8 mg/kg);IVM + LEV, simultaneously treated with IVM and LEV (two subcutaneous injections atthe same dose rates). Seven animals from each treated group (farm C) were randomlyselected to perform the PK study. Drug concentrations were measured by HPLC. Thetherapeutic response (efficacy) was determined at 14 days after treatment by the fecal eggreduction test. Results: The mean area under the concentration vs time curve (AUC) forIVM obtained after administration of IVM alone (274 ± 65.1 ng.d/mL) was similar to thatobtained when IVM was co-administered with LEV (295 ± 111 ng.d/mL). Likewise, meanLEV AUC values were similar after LEV administration alone (8.90 ± 2.69 µg.h/mL) orcombined with IVM (9.11 ± 1.82 µg.h/mL). No adverse PK interactions were observedafter the combined treatment, with similar PK parameters (p > 0.05) obtained betweenthe single-drug and the combination-based strategies. On farm A, the overall fecal eggreductions were 38% (IVM), 99% (LEV) and 100% (IVM + LEV). While Cooperia spp. andHaemonchus spp. showed reduced susceptibility to IVM treatment, LEV demonstratedhigh efficacy against both genera, with only a minimal proportion of Haemonchus spp.remaining after treatment. Similarly, total fecal egg reductions were 42% (IVM), 99% (LEV)and 100% (IVM + LEV) on farm B, and 54% (IVM), 99% (LEV) and 100% (IVM + LEV) onfarm 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 moleculeswas the only treatment that achieved 100% efficacy against all nematode genera (Cooperia,Ostertagia, Haemonchus and Oesophagostomum spp.). Conclusions: Based on the describedPK and pharmacodynamic (PD) assessments, the IVM + LEV combination appears to bea promising pharmacological option for controlling resistant gastrointestinal nematodesin cattle, with the additional potential to delay the progression of nematode anthelmintic resistance. Overall, the study provides original and robust pharmacokinetic and efficacy data that contribute to the optimization of parasite control strategies in cattle. This drug combination strategy may enhance treatment efficacy and contribute to improved parasite control in cattle production systems.