Macrofilaricidal efficacy of single and repeated oral and subcutaneous doses of flubendazole in Litomosoides sigmodontis infected jirds

Abstract

Flubendazole (FBZ) is highly efficacious against filarial nematodes after parenteral administration and presents a promising macrofilaricidal drug candidate for the elimination of onchocerciasis and other filariae. In the present study the efficacy of a newly developed bioavailable amorphous solid dispersion (ASD) oral formulation of FBZ was investigated in the Litomosoides sigmodontis jird model. FBZ was administered to chronically infected, microfilariae-positive jirds by single (40mg/kg), repeated (2, 6 or 15mg/kg for 5 or 10 days) oral (OR) doses or single subcutaneous (SC) injections (2 or 10mg/kg). Jirds treated with 5 SC injections at 10mg/kg served as positive controls, with untreated animals used as negative controls. After OR doses, FBZ is rapidly absorbed and cleared and the exposures increased dose proportionally. SC administered FBZ was slowly released from the injection site and plasma levels remained constant up to necropsy eight weeks after treatment end. Increasing single SC doses caused less than dose-proportional exposures. At necropsy, all animals receiving 1x or 5x 10mg/kg SC FBZ had cleared all adult worms and the 1x 2mg/kg SC treatment had reduced the adult worm burden by 98%. 10x 15mg/kg OR FBZ reduced the adult worm burden by 95%, whereas 1x 40mg/kg and 5x 15mg/kg OR reduced the worm burden by 85 and 84%, respectively. Microfilaremia was completely cleared at necropsy in all animals of the SC treatment regimens, while all oral FBZ treatment regimens reduced the microfilaremia by >90% in a dose and duration dependent manner. In accordance, embryograms from female worms revealed a FBZ dose and duration dependent inhibition of embryogenesis. Histological analysis of the remaining female adult worms showed that FBZ had damaged the body wall, intestine and most prominently the uterus and uterine content. Results of this study demonstrate that single and repeated SC injections and repeated oral administrations of FBZ have an excellent macrofilaricidal effect.

Oxfendazole mediates macrofilaricidal efficacy against the filarial nematode Litomosoides sigmodontis in vivo and inhibits Onchocerca spec. motility in vitro

“…This phenomenon was also shown with flubendazole in jirds infected with L . sigmodontis and histological analyses suggested that flubendazole causes pathological changes in the female worm intestine, body wall, uterus and uterine content, which were arguably defined as permanent [ 17 ].…”

“…Thus, the L . sigmodontis rodent model was chosen by the Bill & Melinda Gates Foundation for the “Macrofilaricidal Drug Accelerator Program” to identify new compounds with a macrofilaricidal effect [ 17 , 23 – 25 , 54 , 55 ]. Despite this, all filarial rodent models have a shorter filarial life-span in comparison to human pathogenic filariae and differences in the location of the parasites and the associated accessibility of the drug to the filariae (thoracic cavity for L .…”

“…The L . sigmodontis rodent model has been used to validate macrofilaricidal drug candidates by a consortium led by the Bill & Melinda Gates Foundation, Drugs for Neglected Diseases initiative (DND i ), academia, and pharmaceutical companies and has supported the advancement of a few macrofilaricidal compounds through preclinical and clinical development [ 17 , 22 – 28 ]. In this study we demonstrate that oxfendazole exhibits excellent macrofilaricidal efficacy following both oral and sc administrations in the L .…”

Efficacy of subcutaneous doses and a new oral amorphous solid dispersion formulation of flubendazole on male jirds (Meriones unguiculatus) infected with the filarial nematode Brugia pahangi

“…The selection of formulation took into account the feasibility and stability of the formulation and exposures. The ASD formulation was also tested in another study with female jirds infected with Litomosoides sigmodontis at the same oral doses of 6 and 15 mg/kg for 5 days [32]. At Day 5, the exposures in the present study were 2–3 fold lower than the Hübner study.…”

“…Hübner et al observed histological damage in female Litomosoides sigmodontis from jirds given oral ASD FBZ doses of 6 and 15 mg/kg for 5 days and with 2 and 6 mg/kg for 10 days [32]. Degenerative changes were seen in the body wall, intestine and uteri, with major structural damage to the developing mf.…”