ive against the immature and mature worms of Fasciola hepatica andFasciola gigantica [see Clinical Studies (14)].
Resistance
Studies in vitro and in vivo as well as case reports suggest a potential for development of resistance totriclabendazole.
The mechanism of resistance may be multifactorial that include changes in drug uptake/efflux mechanisms, thetarget molecules, and altered drug metabolism. The clinical significance of triclabendazole resistance in humansis not established.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Mutagenesis
No genotoxic potential was noted for triclabendazole tested in a battery of 6 genotoxicity in vitro and in vivoassays which include a bacterial reverse mutation assay, chromosome aberration assays, and a micronucleusassay.
Impairment of Fertility
No drug-related effects on reproductive performance, mating ratios or fertility indices have been noted in a2-generation reproductive and developmental toxicity study in rats. The animals were treated with up to 75 ppmtriclabendazole via diet, amounting to a mean daily intake of 7.3 mg/kg/day (approximately 0.1 times theMRHD based on body surface area comparison) for a period of 110 days, which included a 12-day matingperiod beginning on Day 62 of dosing and continuing until the offspring were weaned.
13.2 Animal Toxicology and/or Pharmacology
Dietary administration of triclabendazole at a dose of 39 mg/kg/day (1.1-times the MRHD based on bodysurface area comparison) was associated with a transient increase in the QT and QTc intervals on weeks 5 and 9in some dogs in a 13-week study resulting in QT (QTc) intervals of 212-227 (318-338) msec in the 39 mg/kgdose group (adjusted) compared to 190-193 (280-297) msec in controls. At Week 13, no statistically significantdifferences 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 2.7times the MRHD based on body surface area comparison),increase in QTc intervals was observed resulting inQTc 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 100-500times 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 andnucleated red cell counts were observed at 39 mg/kg/day (1.1 times the MRHD based on body surface areacomparison) predominantly at week 9 of dosing.
14 CLINICAL STUDIES
An open label, randomized trial, conducted in Vietnam compared the efficacy of triclabendazole (two 10 mg/kgdoses given 12 hours apart with food) to oral artesunate (4 mg/kg, given once daily for 10 days). One hundredpatients (age range: 9-74 years) with acute symptomatic fascioliasis were randomized, 50 in each treatment group. At 3 months after treatment, 92% and 76% (difference 16%; 95% CI [1.7, 30.8], p = 0.035) of patients inthe triclabendazole and artesunate arms respectively, reported no clinical symptoms.
The clinical development program of triclabendazole for the treatment of fascioliasis included 6 nonrandomized,open label studies performed in Cuba, Bolivia, Peru, Chile, and Iran in a total of 245 adult andpediatric patients with stool-confirmed fascioliasis. All studies were similar in design. The |
