Triclabendazole

Triclabendazole is an anthelmintic against Fasciola species.

Triclabendazole exposure-response relationships and the time course of pharmacodynamics response are unknown.

After oral administration of a single dose of 10 mg/kg triclabendazole with a 560-kcal meal to patients with fascioliasis, mean peak plasma concentrations (C_max) for triclabendazole, the sulfoxide and sulfone metabolites were 1.16, 38.6, and 2.29 μmol/L, respectively. The area under the curve (AUC) for triclabendazole, the sulfoxide and sulfone metabolites were 5.72, 386, and 30.5 μmol∙h/L, respectively.

Absorption

Following oral administration of a single dose of triclabendazole at 10 mg/kg with a 560-kcal meal to patients with fascioliasis, the median T_max for the parent compound and the sulfoxide metabolite was 3 to 4 hours.

Effect of Food

C_max and AUC of triclabendazole and sulfoxide metabolite increased approximately 3-fold and 2-fold respectively 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 T_max increased from 2 hours in the fasted state to 4 hours in the fed state.

Distribution

The apparent volume of distribution (V_d) 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 (t_1/2) of triclabendazole, the sulfoxide and sulfone metabolites in humans is approximately 8, 14, and 11 hours, respectively.

Metabolism

Based on in vitro studies, triclabendazole is primarily metabolized by CYP1A2 (approximately 64%) into its active sulfoxide metabolite and to a lesser extent by CYP2C9, CYP2C19, CYP2D6, CYP3A, and FMO. This sulfoxide metabolite is further metabolized primarily by CYP2C9 to the active sulfone metabolite and to a lesser 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 tract in the feces (90%), together with the sulfoxide and sulfone metabolite. Less than 10% of an oral dose is excreted in the urine.

Specific Populations

The pharmacokinetics of triclabendazole 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 20 patients, 7 children (ages 9 to 15 years) were dosed with triclabendazole 10 mg/kg single dose. AUC values of triclabendazole 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 of triclabendazole and its metabolites to induce CYP enzymes. No in vitro studies were conducted to assess the ability of triclabendazole and its metabolites to induce or inhibit transporters.

Dietary administration of triclabendazole at a dose of 39 mg/kg/day (1.1-times the MRHD based on body surface area comparison) was associated with a transient increase in the QT and QTc intervals on weeks 5 and 9 in some dogs in a 13-week study resulting in QT (QTc) intervals of 212-227 (318-338) msec in the 39 mg/kg dose group (adjusted) compared to 190-193 (280-297) msec in controls. At Week 13, no statistically significant differences were noted between the treatment and control groups.

Additionally, when dogs were administered triclabendazole at a single dose of 40 or 100 mg/kg (1.1 or 2.7 times the MRHD based on body surface area comparison), increase in QTc intervals was observed resulting in QTc intervals of 217-247 msec compared to a normal (historical control) of 193-231 msec. However, plasma levels of the sulfone metabolite in dogs (which is thought to mediate QTc prolongation) was about 100-500 times the plasma level of the sulfone metabolite measured in human plasma.

In the 13-week study in beagle dogs, slight anemia accompanied by minimal increases in reticulocyte and nucleated red cell counts were observed at 39 mg/kg/day (1.1 times the MRHD based on body surface area comparison) predominantly at week 9 of dosing.