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

PLoS Negl Trop Dis. 2019 Jan 16;13(1):e0006356. doi: 10.1371/journal.pntd.0006356. eCollection 2019 Jan.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Brugia malayi / drug effects*
  • Disease Models, Animal
  • Filaricides / administration & dosage
  • Filaricides / pharmacology*
  • Ivermectin / administration & dosage
  • Ivermectin / pharmacology
  • Male
  • Mebendazole / administration & dosage
  • Mebendazole / analogs & derivatives*
  • Mebendazole / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Microfilariae / drug effects*
  • Onchocerca / drug effects*
  • Onchocerciasis / drug therapy*
  • Parasite Load

Substances

  • Filaricides
  • Ivermectin
  • Mebendazole
  • flubendazole

Grants and funding

This work was funded by Janssen Pharmaceutica contracts [ICD 878818 / ICD 890534] and a Bill and Melinda Gates Foundation Grand Challenges Explorations Grant [OPP1119043] to JDT, MJT and SW. The funders had a role in the study design, pharmacokinetic analysis and manuscript prepartion.