f Food
Cmax and AUC of triclabendazole and sulfoxide metabolite increased approximately 3-fold and 2-foldrespectively when triclabendazole was administered as a single dose at 10 mg/kg with a meal containing a total of approximately 560 kcal (consisting of 2 cups of sweetened white coffee, a roll with cheese, and a roll with
butter and jam). In addition, the sulfoxide metabolite Tmax increased from 2 hours in the fasted state to 4 hours
in the fed state.
Distribution
The apparent volume of distribution (Vd) of the sulfoxide metabolite in fed patients is approximately 1 L/kg.Protein-binding of triclabendazole, sulfoxide metabolite and sulfone metabolite in human plasma was 96.7%,98.4% and 98.8% respectively.
Elimination
The plasma elimination half-life (t1/2) of triclabendazole, the sulfoxide and sulfone metabolites in humans isapproximately 8, 14, and 11 hours, respectively.
Metabolism
Based on in vitro studies, triclabendazole is primarily metabolized by CYP1A2 (approximately 64%) into itsactive sulfoxide metabolite and to a lesser extent by CYP2C9, CYP2C19, CYP2D6, CYP3A, and FMO. Thissulfoxide metabolite is further metabolized primarily by CYP2C9 to the active sulfone metabolite and to alesser extent by CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6 and CYP3A4, in vitro.
Excretion
No excretion data is available in humans. However, in animals, the drug is largely excreted via the biliary tractin the feces (90%), together with the sulfoxide and sulfone metabolite. Less than 10% of an oral dose isexcreted in the urine.
Specific Populations
The pharmacokinetics of EGATEN were not studied in patients with renal or hepatic impairment.
Pediatric Patients
No dedicated pediatric pharmacokinetic studies were conducted. However, in one pharmacokinetic study of 20patients, 7 children (ages 9 to 15 years) were dosed with triclabendazole 10 mg/kg single dose. AUC values oftriclabendazole sulfoxide were 20% lower in these pediatric patients in the fed state than in the 13 patients
above 15 years of age, but the difference was not statistically significant.
Drug Interaction Studies:
Clinical drug interaction studies have not been conducted for triclabendazole.
In Vitro Studies
Triclabendazole and its sulfoxide and sulfone metabolites have the potential to inhibit CYP1A2, CYP2A6,CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A at clinically relevant plasma concentrations,with the highest potential of inhibition on CYP2C19. No in vitro studies were conducted to assess the ability oftriclabendazole and its metabolites to induce CYP enzymes. No in vitro studies were conducted to assess theability of triclabendazole and its metabolites to induce or inhibit transporters.
12.4 Microbiology
Mechanism of Action
The mechanism by which triclabendazole exhibits its effect against Fasciola species is not fully elucidated.
Studies in vitro and/or in infected animals suggest that triclabendazole and its active metabolites (sulfoxide andsulfone) are absorbed by the tegument of the immature and mature worms, leading to a decrease of the restingmembrane potential, inhibition of tubulin function as well as protein and enzyme synthesis. These metabolic disturbances are associated with inhibition of motility, disruption of the surface as well as ultrastructure thatincludes inhibition of spermatogenesis and vitelline cells.
Antimicrobial Activity
Triclabendazole and its metabolites are act |
