title: 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.
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland; University of Basel, CH-4003 Basel, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Meister
authors.forename: Urs
authors.initials: U
authors.lastname: Duthaler
authors.forename: Jörg
authors.initials: J
authors.lastname: Huwyler
authors.forename: Laura
authors.initials: L
authors.lastname: Rinaldi
authors.forename: Antonio
authors.initials: A
authors.lastname: Bosco
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cringoli
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keiser
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000871:Anthelmintics / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D005210:Fasciola hepatica; D005211:Fascioliasis / Q000188:drug therapy / Q000662:veterinary*; D006207:Half-Life; D015394:Molecular Structure; D015203:Reproducibility of Results; D012756:Sheep; D012757:Sheep Diseases / Q000188:drug therapy / Q000469:parasitology*; D013141:Spiro Compounds / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000871:Anthelmintics; C000588639:MT04 compound; C518172:OZ78 compound; D013141:Spiro Compounds; D000218:Adamantane
keywords: Fasciola hepatica; LC–MS/MS; MT04; OZ78; Pharmacokinetics; Sheep