Oxfendazole repurposing as a flukicidal compound

CEBALLOS, L; MORENO, L; CANTON, C; DOMINGUEC, P; LANUSSE, C; GAYO, V; ALVAREZ, L

Daegu

Congreso; International Congress of Parasitology (ICOPA); 2018

ICOPA

Introduction: Fascioliasis is a zoonotic parasitic disease caused by Fasciola hepatica affecting 2.4 million people worldwide and causing enormous production losses in livestock animals. Control based on the indiscriminate use of chemotherapy resulted in the development of resistance to most effective flukicidal drugs (e.g Triclabendazole). Oxfendazole (OFZ) is a well established nematodicidal drug. However, in an attempt to repurpose its use, promissory flukicidal efficacies have been observed when OFZ was used at higher dose rates both in sheep and pigs. Objectives: 1) to compare the plasma pharmacokinetic (PK) profiles obtained after administration of different OFZ doses in sheep, and 2) to evaluate the dose-related pattern of in vivo accumulation of OFZ/metabolites into F. hepatica. 1) Pharmacokinetic trial: sheep (n=12) were orally treated with OFZ at either 5 (OFZ5) or 30 (OFZ30) mg/kg. Blood samples were collected over 96 h p.t., 2) Drug accumulation trial: F. hepatica infected animals (n=8) were orally treated with OFZ at either 5 or 30mg/kg. Samples of blood, bile, liver and adult liver flukes were obtained from sacrificed infected sheep. OFZ/metabolites were analyzed for by HPLC. Results and conclusions: OFZ was the main analyte recovered in plasma. The Cmax and AUC0-t values were approx. 4-fold higher in the OFZ30 group, compared to that observed in OFZ5 group. OFZ accumulation into F. hepatica resulted 332 % higher after the 30 mg/kg dose (4.28 µg/g) compared to the lower dose (0.99 µg/g). OFZ dose increment correlated with a higher systemic drug exposure and accumulation within target trematode parasite, which would explain its excellent efficacy against F. hepatica at the dose of 30 mg/kg. These pharmacological data contribute to assess OFZ repurposing for a new use in liver flukes control.