Graphical abstractHighlights► Macrocyclic lactones share some structural and physico-chemical properties. ► The kinetic-dynamic differences of these compounds should be addressed under in vivo standardized conditions. ► Lower concentrations of moxidectin were obtained in resistant Haemonchus contortus. ► Moxidectin showed a higher efficacy against resistant H. contortus. ► The P-glycoprotein expression in H. contortus was increased after ivermectin treatment.

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Mixtures of drugs from different chemical families have been proposed as a valid strategy to delay the development of anthelmintic resistance. The current work summarizes the outcome of the evaluation of the plasma disposition kinetics of albendazole (ABZ) and ivermectin (IVM) administered either alone or co-administered to lambs infected with gastrointestinal (GI) nematodes resistant to both anthelmintic molecules. Thirty six (36) Corriedale lambs naturally infected with multiple resistant GI nematodes were allocated into six treatment groups: (a) ABZ intravenous (ABZ(IV)); (b) IVM(IV); (c) ABZ(IV) + IVM(IV); (d) ABZ intraruminal (IR); (e) IVM subcutaneous (SC) and (f) ABZ(IR) + IVM(SC). Plasma samples were collected over 15 days post-treatment and analysed by HPLC. The estimated pharmacokinetic (PK) parameters were statistically compared using parametric and non-parametric statistical tests. The presence of IVM did not affect the plasma disposition kinetics of ABZ and its metabolites after the i.v. administration. However, the ABZ sulphoxide (ABZSO) area under the concentration vs. time curve (AUC) was significantly lower (P < 0.01) after the intraruminal (i.r.) administration of ABZ alone compared to that obtained for the combined treatment with IVM [subcutaneous (s.c.) injection]. The IVM plasma AUC obtained after its i.v. co-administration with ABZ was 88% higher (P < 0.05) compared to the treatment with IVM alone. Any marked difference on IVM PK parameters was observed between the treatments ABZ + IVM and IVM alone injected subcutaneously. The data obtained here indicate that the co-administration of ABZ and IVM does not induce an adverse kinetic interaction. This type of pharmacology-based evaluation of drug interactions is becoming highly relevant as drug combinations are now widely used as an alternative to control resistant helminth parasites in livestock.

Administration of IVM and MXD at 0.4 compared with 0.2 mg/kg accounted for enhanced drug exposure in the target tissues, as well as higher drug concentrations within resistant nematodes. The current work is a further contribution to the evaluation of the relationship between drug efficacy and basic pharmacological issues in the presence of resistant parasite populations.

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