Pharmacokinetics and efficacy of large ivermectin doses in lambs parasitized with resistant Haemonchus contortus

Abstract

The main goals of the current work were: a) to assess the ivermectin (IVM) plasma disposition kinetics after its administration at the recommended, x5 and x10 times dose rates to lambs and, b) to compare the clinical efficacy of the same IVM dosages in lambs infected with an IVM-resistant strain of Haemonchus contortus. There was two separated trials, where IVM was administered either subcutaneously (Experiment I) or intraruminally (Experiment II). Each experiment involved twenty-four (24) lambs artificially infected with a highly resistant H. contortus strain. Animals were allocated into 4 groups (n=6) and treated with IVM at either 0.2 (IVMx1), 1 (IVMx5) or 2 mg/kg (IVMx10). Plasma samples were collected up-to 12 days post-treatment and analysed by HPLC. An untreated-control Group was included to assess the comparative anthelmintic efficacy of the different treatments. Parametric and non-parametric tests were used to compare the statistical significance of the results (P<0.05). After the subcutaneous treatment, the IVM plasma area under the concentration-time curve (AUC) increased from 41.9 (IVMx1) up to 221 (IVMx5) and 265 ng.day/mL (IVMx10), indicating some type of non-proportionality in the dose-systemic exposure relationship. Consistently, the efficacies against resistant H. contortus after the subcutaneous treatment were 44% (IVMx1), 75% (ABZx5) and 76% (ABZx10). However, the intraruminal IVM treatment reached clinical efficacies ranging from 48 (IVMx1) up to 96 (IVMx5), and 98% (IVMx10). The large IVM concentrations achieved at the abomasal content after its intraruminal/oral administration compared to the subcutaneous injection (Lloberas et al, 2011), may have accounted for a greater amount of drug reaching the adult parasite. An enhanced abomasal drug exposure may explain the improved efficacy against this recalcitrant H. contortus strain observed only after the intraruminal administration at 5 and 10-fold the IVM therapeutic dosage.