Efficacy and pharmacokinetics of OZ78 and MT04 against a natural infection with Fasciola hepatica in sheep

Abstract

Fasciolosis is a parasitosis caused by the food-borne trematode Fasciola spp. of major veterinary significance. Triclabendazole is the first line treatment in humans and animals but cases of resistance are spreading worldwide. The synthetic peroxides OZ78 and MT04 are lead compounds for the treatment of fasciolosis. In the present study we investigated the efficacy and drug disposition following a single intramuscular dose of 100 mg/kg OZ78 and MT04 in sheep harbouring a natural Fasciola hepatica infection. A liquid chromatography and tandem mass spectrometry (LC-MS/MS) method was developed and validated to quantify plasma and bile concentrations of both compounds. Plasma samples were analysed with an accuracy for OZ78 and MT04 from 91 to 115% and a precision lower than 8.9%. Bile samples displayed an accuracy between 92 and 101% and a precision up to 12.7%. Bile samples were collected at 0 and 6h post-administration. Plasma mean peak concentration was 11.1 μg/ml at 1.5 h for OZ78 and 4.8 μg/ml at 4.2 h for MT04. Mean AUC of OZ78 and MT04 was 6698 and 3567 μg min/ml, respectively. Bile concentration at 6h post-treatment was 1.0 μg/ml for OZ78 and 1.4 μg/ml for MT04. Treatment with OZ78 showed no effect on egg burden and adult worm counts in vivo, whereas MT04 displayed a significant egg count reduction of 98.5% and a worm burden reduction of 92%. In conclusion, our study reveals an excellent activity of MT04 against F. hepatica in naturally infected sheep and a first insight into its PK behaviour.

Keywords: Fasciola hepatica; LC–MS/MS; MT04; OZ78; Pharmacokinetics; Sheep.