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

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Sjoberg, Hanna ORCID: https://orcid.org/0000-0003-1948-6779, Pionnier, Nicolas ORCID: https://orcid.org/0000-0002-2379-4945, Aljayyoussi, Ghaith, Metuge, Haelly, Njouendou, Abdel, Chunda, Valerine C., Fombad, Fanny F., Tayong, Dizzle B., Gandjui, Narcisse V. T., Akumtoh, Desmond N., Chounna, Patrick W. N., Ndzeshang, Bertrand L., Lachaud, Sophie, Tekle, Fetene, Quirynen, Ludo, Engelen, Marc, Baeten, Benny, Steven, Andrew, Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192, Taylor, Mark, Wanji, Samuel and Turner, Joseph ORCID: https://orcid.org/0000-0002-2185-5476 (2019) 'Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models'. PLoS Neglected Tropical Diseases, Vol 13, Issue 1, e0006356.

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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.

Item Type: Article
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 253 Anthelmintics
QX Parasitology > Helminths. Annelida > QX 301 Filarioidea
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 880 Filariasis and related conditions (General)
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI): https://doi.org/10.1371/journal.pntd.0006356
SWORD Depositor: JISC Pubrouter
Depositing User: Stacy Murtagh
Date Deposited: 17 Jan 2019 12:54
Last Modified: 18 Jan 2019 13:06
URI: https://archive.lstmed.ac.uk/id/eprint/9980

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