Modulation of metabolic and transport processes: a valuable tool for improving anthelmintic efficacy?

Abstract

In vivo modulation of drug metabolizing enzymes and transporters may delay the elimination and enhance the systemic availability of anthelmintic compounds. Parasite exposure to the active molecules can be enhanced through their combination with transport modulators or other active anthelmintics. However, the practical relevance of such interactions is unknown. This work aims at assessing the occurrence of PK/PD interactions between (a) oxfendazole and triclabendazole; (b) moxidectin and loperamide; and (c) abamectin and ivermectin/itraconazole in lambs.Materials and MethodsLambs parasitized with nematodes highly resistant to benzimidazole and macrocyclic lactones were used.Experiment 1: Lambs (three groups, n=7 each) were treated with oxfendazole (5 mg/kg PO), triclabendazole (12 mg/kg PO) or their combination;Experiment 2: Lambs (two groups, n=7 each) were treated with moxidectin (0.2 mg/kg SC) alone or in combination with loperamide (0.16 mg/kg PO) and pluronic 123;Experiment 3: Lambs (two groups, n=10 each) were treated with abamectin (0.2 mg/kg SC) alone or in combination with ivermectin (0.2 mg/kg SC) and itraconazole (30 mL PO). Drug/metabolite concentrations in plasma were measured (days 0-15). The faecal egg count reduction test (FECRT) was used as a measure of nematodicidal efficacy.ResultsExperiment 1: Coadministration resulted in an increase in both the plasma AUC0-LOQ and MRT of the metabolite fenbendazole sulfone (p<0.05), whereas all the PK parameters for triclabendazole sulfone were significantly decreased. Efficacy rose from 47.2 and 55.4 % (single administration) to 75.7 % (coadministration).Experiment 2: No differences in PK parameters were observed upon coadministration. Efficacies were 77.1 and 71.2 %, respectively, for the single and combined treatments. Experiment 3: Exposure to ivermectin and itraconazole resulted in an increase in abamectin Cmax and AUC0-LOQ (not significant). Efficacies were 0 % for both treatments.ConclusionsCombination of active principles with modulators and other active compounds has been advocated as an alternative to enhance anthelmintic efficacy. However, clinical efficacy against resistant nematodes remains elusive in practical terms. In spite of proven in vitro pharmacological interactions, translation to clinical settings shows that in vivo trials are needed in order to assess the real impact of modulators and combined therapies in parasite control.