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(2019)
摘要
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. Author summary Onchocerciasis, caused by the filarial parasitic worm, Onchocerca volvulus, is a major cause of infection-related blindness and skin disease and is targeted for elimination. Current drugs are not optimal in all patient populations and a short-course cure would accelerate elimination. Flubendazole is used to treat intestinal worms in humans. The current oral formulation is not well absorbed into the blood. Flubendazole treatment has mediated curative efficacy in onchocerciasis patients when given as an injection but also causes adverse reactions at the injection site. In this study, we tested whether a new oral formulation of flubendazole with improved absorption could selectively kill Onchocerca adult parasites compared with circulating larval filarial parasites, using immunodeficient mouse models. Whilst injections of flubendazole mediated high levels of efficacy, five-day oral treatment, at a range of doses, did not emulate this curative effect. Oral flubendazole also did not significantly affect levels of microfilariae in the blood. After comparing levels of flubendazole in the blood following injection versus oral treatment, we conclude that a long duration, low dose of the oral formulation, for 5 weeks, would be needed to match the exposure of the drug following injection.
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