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

Fischer, Chelsea; Urriza, Iosune Ibiricu; Bulman, Christina; Lim, K. C.; Gut, Jiří; Lachau‐Durand, Sophie; Engelen, Marc; Quirynen, Ludo; Tekle, Fetene; Baeten, Benny; Beerntsen, Brenda T.; Lustigman, Sara; Sakanari, Judy

doi:10.1371/journal.pntd.0006787

Cited by 13 publications

(12 citation statements)

References 39 publications

(42 reference statements)

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“…FBZ formulated as an ASD is orally bioavailable and was used for initial toxicological investigations (Longo et al 2014;Tweats et al 2016). Following encouraging in vivo efficacy results, Janssen Pharmaceutica further evaluated the orally available ASD formulation of FBZ and demonstrated macrofilaricidal in vivo efficacy (Fischer et al 2019;Sjoberg et al 2019;Hübner et al 2019a, b). Despite these encouraging results, efficacious concentrations were associated with toxicity.…”

Section: Flubendazole (Fbz)mentioning

confidence: 99%

Onchocerciasis drug development: from preclinical models to humans

2021

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Twenty diseases are recognized as neglected tropical diseases (NTDs) by World Health Assembly resolutions, including human filarial diseases. The end of NTDs is embedded within the Sustainable Development Goals for 2030, under target 3.3. Onchocerciasis afflicts approximately 20.9 million people worldwide with > 90% of those infected residing in Africa. Control programs have made tremendous efforts in the management of onchocerciasis by mass drug administration and aerial larviciding; however, disease elimination is not yet achieved. In the new WHO roadmap, it is recognized that new drugs or drug regimens that kill or permanently sterilize adult filarial worms would significantly improve elimination timelines and accelerate the achievement of the program goal of disease elimination. Drug development is, however, handicapped by high attrition rates, and many promising molecules fail in preclinical development or in subsequent toxicological, safety and efficacy testing; thus, research and development (R&D) costs are, in aggregate, very high. Drug discovery and development for NTDs is largely driven by unmet medical needs put forward by the global health community; the area is underfunded and since no high return on investment is possible, there is no dedicated drug development pipeline for human filariasis. Repurposing existing drugs is one approach to filling the drug development pipeline for human filariasis. The high cost and slow pace of discovery and development of new drugs has led to the repurposing of “old” drugs, as this is more cost-effective and allows development timelines to be shortened. However, even if a drug is marketed for a human or veterinary indication, the safety margin and dosing regimen will need to be re-evaluated to determine the risk in humans. Drug repurposing is a promising approach to enlarging the pool of active molecules in the drug development pipeline. Another consideration when providing new treatment options is the use of combinations, which is not addressed in this review. We here summarize recent advances in the late preclinical or early clinical stage in the search for a potent macrofilaricide, including drugs against the nematode and against its endosymbiont, Wolbachia pipientis.

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Section: Flubendazole (Fbz)mentioning

confidence: 99%

Onchocerciasis drug development: from preclinical models to humans

2021

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“…A detailed list of these studies is shown in S1 Table . Flubendazole and oxfendazole have excellent macrofilaricidal efficacy when administered subcutaneously (sc), while efficacy of flubendazole was reduced when used via the oral route (S1 Table [8,[11][12][13][14]). Although the efficacy of flubendazole against several filarial nematodes was validated in many studies [15][16][17], Janssen Pharmaceutica decided not to proceed with flubendazole in human clinical studies based on the toxicological profile [18]. Oxfendazole, on the other hand, was shown to be efficacious for the treatment of Taenia solium cysticercosis-infected pigs [19].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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A major impediment to eliminate lymphatic filariasis and onchocerciasis is the lack of effective short-course macrofilaricidal drugs or regimens that are proven to be safe for both infections. In this study we tested oxfendazole, an anthelmintic shown to be well tolerated in phase 1 clinical trials. In vitro , oxfendazole exhibited modest to marginal motility inhibition of adult worms of Onchocerca gutturosa , pre-adult worms of Onchocerca volvulus and Onchocerca lienalis microfilariae. In vivo , five days of oral treatments provided sterile cure with up to 100% macrofilaricidal efficacy in the murine Litomosoides sigmodontis model of filariasis. In addition, 10 days of oral treatments with oxfendazole inhibited filarial embryogenesis in patent L . sigmodontis -infected jirds and subsequently led to a protracted but complete clearance of microfilaremia. The macrofilaricidal effect observed in vivo was selective, as treatment with oxfendazole of microfilariae-injected naïve mice was ineffective. Based on pharmacokinetic analysis, the driver of efficacy is the maintenance of a minimal efficacious concentration of approximately 100 ng/ml (based on subcutaneous treatment at 25 mg/kg in mice). From animal models, the human efficacious dose is predicted to range from 1.5 to 4.1 mg/kg. Such a dose has already been proven to be safe in phase 1 clinical trials. Oxfendazole therefore has potential to be efficacious for treatment of human filariasis without causing adverse reactions due to drug-induced microfilariae killing.

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“…Limitations of our study are due to the usage of surrogate filarial species in animal models for the preclinical analysis of drugs intended for human filariasis, with filarial species that may possess a different susceptibility for the drug candidates, altered PK/PD relations in the rodent hosts and differences in the anatomical locations where the adult filariae are found. Nevertheless, L. sigmodontis and Brugia rodent models have been used in a range of preclinical studies, including a human progression study with the preclinical candidate ABBV-4083 (DNDi, 2019; Fischer et al, 2019; Hong et al, 2019; Hübner et al, 2019a; Jacobs et al, 2019; Taylor et al, 2019). Doxycycline, the first proven safe macrofilaricidal treatment for human filariasis was also tested in the L. sigmodontis model and was comparable to what was found in human studies (Hoerauf et al, 1999), i.e.…”

Section: Discussionmentioning

confidence: 99%

Short-course quinazoline drug treatments are effective in the Litomosoides sigmodontis and Brugia pahangi jird models

Hübner

Gunderson

Vogel

et al. 2020

International Journal for Parasitology: Drugs and Drug Resistan

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The quinazolines CBR417 and CBR490 were previously shown to be potent anti-wolbachials that deplete Wolbachia endosymbionts of filarial nematodes and present promising pre-clinical candidates for human filarial diseases such as onchocerciasis. In the present study we tested both candidates in two models of chronic filarial infection, namely the Litomosoides sigmodontis and Brugia pahangi jird model and assessed their long-term effect on Wolbachia depletion, microfilariae counts and filarial embryogenesis 16−18 weeks after treatment initiation (wpt). Once per day (QD) oral treatment with CBR417 (50 mg/kg) for 4 days or twice per day (BID) with CBR490 (25 mg/kg) for 7 days during patent L. sigmodontis infection reduced the Wolbachia load by >99% and completely cleared peripheral microfilaremia from 10–14 wpt. Similarly, 7 days of QD treatments (40 mg/kg) with CBR417 or CBR490 cleared >99% of Wolbachia from B. pahangi and reduced peritoneal microfilariae counts by 93% in the case of CBR417 treatment. Transmission electron microscopy analysis indicated intensive damage to the B. pahangi ovaries following CBR417 treatment and in accordance filarial embryogenesis was inhibited in both models after CBR417 or CBR490 treatment. Suboptimal treatment regimens of CBR417 or CBR490 did not lead to a maintained reduction of the microfilariae and Wolbachia load. In conclusion, CBR417 or CBR490 are pre-clinical candidates for filarial diseases, which achieve long-term clearance of Wolbachia endosymbionts of filarial nematodes, inhibit filarial embryogenesis and clear microfilaremia with treatments as short as 7 days.

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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

Cited by 13 publications

References 39 publications

Onchocerciasis drug development: from preclinical models to humans

Onchocerciasis drug development: from preclinical models to humans

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

Short-course quinazoline drug treatments are effective in the Litomosoides sigmodontis and Brugia pahangi jird models

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