Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models.
Administration, Oral
Animals
Brugia malayi
/ drug effects
Disease Models, Animal
Filaricides
/ administration & dosage
Ivermectin
/ administration & dosage
Male
Mebendazole
/ administration & dosage
Mice
Mice, Inbred BALB C
Mice, SCID
Microfilariae
/ drug effects
Onchocerca
/ drug effects
Onchocerciasis
/ drug therapy
Parasite Load
Journal
PLoS neglected tropical diseases
ISSN: 1935-2735
Titre abrégé: PLoS Negl Trop Dis
Pays: United States
ID NLM: 101291488
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
22
12
2017
accepted:
28
02
2018
entrez:
17
1
2019
pubmed:
17
1
2019
medline:
15
2
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 30650071
doi: 10.1371/journal.pntd.0006356
pii: PNTD-D-17-02080
pmc: PMC6334903
doi:
Substances chimiques
Filaricides
0
Ivermectin
70288-86-7
Mebendazole
81G6I5V05I
flubendazole
R8M46911LR
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0006356Déclaration de conflit d'intérêts
Sophie Lachaud, Fetene Tekle, Ludo Quirynen, Marc Engelen, and Benny Baeten are paid employees of Janssen, developed flubendazole and hold patent applications for flubendazole. Joseph D. Turner and Mark J. Taylor received funding for this study by Janssen.
Références
Lancet. 1983 Jan 22;1(8317):139-43
pubmed: 6130195
PLoS Negl Trop Dis. 2011 Mar 29;5(3):e998
pubmed: 21468315
Acta Trop. 2011 Sep;120 Suppl 1:S100-8
pubmed: 20801094
Parasitology. 2014 Jan;141(1):119-27
pubmed: 23866958
Invest Ophthalmol Vis Sci. 1998 Jun;39(7):1176-82
pubmed: 9620077
PLoS Negl Trop Dis. 2015 May 21;9(5):e0003703
pubmed: 25996946
Int J Parasitol Drugs Drug Resist. 2012 Feb 12;2:20-8
pubmed: 24533268
PLoS Med. 2006 Sep;3(9):e371
pubmed: 17002504
PLoS Negl Trop Dis. 2014 Sep 18;8(9):e3113
pubmed: 25233351
Trends Parasitol. 2003 Nov;19(11):516-22
pubmed: 14580963
Trans R Soc Trop Med Hyg. 1981;75(2):306-7
pubmed: 7303142
J Biol Chem. 2009 Aug 14;284(33):22364-78
pubmed: 19458089
World Health Organ Tech Rep Ser. 1995;852:1-104
pubmed: 7541171
Parasit Vectors. 2009 Jan 21;2(1):7
pubmed: 19154624
J Helminthol. 1988 Sep;62(3):181-94
pubmed: 3192910
PLoS Negl Trop Dis. 2014 May 29;8(5):e2838
pubmed: 24874646
Clin Ther. 1981;4(4):285-90
pubmed: 7332916
Parasit Vectors. 2014 Oct 24;7:472
pubmed: 25338621
Trans R Soc Trop Med Hyg. 1983;77(5):668-70
pubmed: 6659046
Int J Parasitol Drugs Drug Resist. 2015 Jul 07;5(3):135-40
pubmed: 26288741
Philos Trans R Soc Lond B Biol Sci. 2013 Jun 24;368(1623):20120144
pubmed: 23798692
Sci Rep. 2017 Mar 16;7(1):210
pubmed: 28303006
Int J Parasitol. 1988 Nov;18(7):885-936
pubmed: 3066771
Wkly Epidemiol Rec. 2010 Jan 22;85(4):23-8
pubmed: 20095110
Expert Rev Anti Infect Ther. 2011 Aug;9(8):681-95
pubmed: 21819332
Parasitol Today. 1990 Apr;6(4):106
pubmed: 15463310
Reprod Toxicol. 2014 Nov;49:33-42
pubmed: 24994687
Wkly Epidemiol Rec. 2014 Apr 11;89(15):153-60
pubmed: 24754045
Expert Rev Anti Infect Ther. 2011 May;9(5):497-501
pubmed: 21609260
Lancet. 2010 Oct 2;376(9747):1175-85
pubmed: 20739055
PLoS Negl Trop Dis. 2007 Aug 30;1(1):e72
pubmed: 17989786
Am J Vet Res. 1983 Jul;44(7):1329-33
pubmed: 6881670
Lancet. 1997 Jul 5;350(9070):18-22
pubmed: 9217715
Trans R Soc Trop Med Hyg. 1979;73(6):673-6
pubmed: 538808