Pharmacokinetic barriers to oxfendazole flukicidal efficacy

Although oxfendazole (OFZ) has been traditionally used to control nematode parasites in domestic animals and more recently in human medicine, high efficacy against porcine cysticercosis and fasciolosis in both sheep and pigs has been observed when the drug is administered at higher dose levels. In this context, the plasma disposition kinetics and the pattern of drug accumulation in adult Fasciola hepatica was characterized in infected sheep orally treated with OFZ at either the nematodicidal dose of 5 mg/kg (OFZ5) or at a higher dose of 30 mg/kg (OFZ30). OFZ was the main analyte detected in plasma of treated sheep. The systemic exposure (AUC0-LOQ) increased from 17.9 ± 3.71 µg.h/mL at the therapeutic dose to 85.4 ± 22.6 µg.h/mL with the highest dose treatment. The plasma Cmax value was approximately fourfold higher in the OFZ30 compared to the OFZ5 treated animals. The dose-related marked differences in OFZ systemic exposure were reflected in the accumulation into F. hepatica specimens, which was 332% higher in the OFZ30 group (4.28 µg/g) than in the OFZ5 group (0.99 µg/g). The data shown here demonstrate that increasing the OFZ dose is associated with enhanced plasma drug exposure and greater accumulation in the target trematode parasite, which helps to explain the enhanced efficacy of OFZ against adult liver flukes at the 30 mg/kg dose.