Research Article: Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models

Date Published: January 16, 2019

Publisher: Public Library of Science

Author(s): Hanna T. Sjoberg, Nicolas Pionnier, Ghaith Aljayyoussi, Haelly M. Metuge, Abdel J. Njouendou, Valerine C. Chunda, Fanny F. Fombad, Dizzle B. Tayong, Narcisse V. T. Gandjui, Desmond N. Akumtoh, Patrick W. N. Chounna, Bertrand L. Ndzeshang, Sophie Lachaud, Fetene Tekle, Ludo Quirynen, Marc Engelen, Benny Baeten, Andrew Steven, Stephen A. Ward, Mark J. Taylor, Samuel Wanji, Joseph D. Turner, Edward Mitre.

Abstract: The Onchocerca ochengi adult implant and Brugia malayi microfilariemic Severe-Combined Immunodeficient (SCID) mouse models are validated screens to measure macrofilaricidal and microfilaricidal activities of candidate onchocerciasis drugs. The purpose of this study was to assess whether 5 daily sub-cutaneous (s.c.) injections of standard flubendazole (FBZ) suspension (10mg/kg), a single s.c. injection (10mg/kg) or 5 daily repeated oral doses of FBZ amorphous solid dispersion (ASD) formulation (0.2, 1.5 or 15mg/kg) mediated macrofilaricidal efficacy against O. ochengi male worms implanted into SCID mice. The direct microfilaricidal activity against circulating B. malayi microfilariae of single dose FBZ ASD formulation (2 or 40 mg/kg) was also evaluated and compared against the standard microfilaricide, ivermectin (IVM). Systemic exposures of FBZ/FBZ metabolites achieved following dosing were measured by pharmacokinetic (PK) bioanalysis. At necropsy, five weeks following start of FBZ SC injections, there were significant reductions in burdens of motile O. ochengi worms following multiple injections (93%) or single injection (82%). Further, significant proportions of mice dosed following multiple injections (5/6; 83%) or single injection (6/10; 60%) were infection negative (drug-cured). In comparison, no significant reduction in recovery of motile adult O. ochengi adult worms was obtained in any multiple-oral dosage group. Single oral-dosed FBZ did not mediate any significant microfilaricidal activity against circulating B. malayi mf at 2 or 7 days compared with >80% efficacy of single dose IVM. In conclusion, multiple oral FBZ formulation doses, whilst achieving substantial bioavailability, do not emulate the efficacy delivered by the parenteral route in vivo against adult O. ochengi. PK analysis determined FBZ efficacy was related to sustained systemic drug levels rather than achievable Cmax. PK modelling predicted that oral FBZ would have to be given at low dose for up to 5 weeks in the mouse model to achieve a matching efficacious exposure profile.

Partial Text: Onchocerciasis remains a severe public health problem despite the sustained efforts of mass drug administration (MDA) programs aimed at eliminating this vector-borne, parasitic neglected tropical disease [1–3]. Elicited by the filarial nematode Onchocerca volvulus and transmitted by black flies of the genus Simulium, it is endemic in much of Sub-Saharan Africa, as well as more limited foci in Brazil, Venezuela, and The Yemen with 37 million people infected [4, 5]. The pathology associated with onchocerciasis ranges from troublesome skin itching, skin disease (onchodermatitis), to blindness, which is caused by a sclerosing ocular keratitis that affects 0.8 million individuals and is the second cause of infectious blindness after trachoma [5–7]. Onchocercal disease is induced by death of migratory larval microfilariae (mf), causing liberation of inflammatory stimuli including the endosymbiont Wolbachia and inflammatory recruitment of granulocytes [8, 9]. The debilitating symptoms of onchodermatitis and river blindness also cause great economic losses in endemic areas [10].

FBZ has been proposed as a relatively ‘low hanging fruit’ to reformulate and repurpose as an oral Onchocerca macrofilaricide [24, 39]. Delivered as a multiple injection, FBZ is highly potent in mediating rapid death of O. ochengi [33] and O. volvulus in vivo [24, 32]. Additionally, as with other members of the benzimidazole (BZ) class, FBZ is more efficacious at targeting adult Onchocerca rather than Onchocerca mf [24, 40], making it an attractive option for an indication where rapid microfilaricidal activity would want to be avoided (e.g. areas of L. loa co-endemicity).