title: Preclinical studies on the pharmacokinetics, safety, and toxicology of oxfendazole: toward first in human studies.
abstract: A 2-week study in rats identified target organs of oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased white blood cell levels, a class effect of benzimidazole anthelmintics, returned to normal during the recovery period. The no observed adverse effect level was determined to be >5 but <25 mg/kg/d and the maximum tolerated dose 100 mg/kg/d. The highest dose, 200 mg/kg/d, resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after 7 days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma, or rat micronucleus assays nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases.
authors.affiliation: Codd Consulting, LLC, Blue Bell, PA, USA ellen.codd@verizon.net.
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Codd
authors.affiliation: SRI International, Biosciences Division, Menlo Park, CA, USA.
authors.forename: Hanna H
authors.initials: HH
authors.lastname: Ng
authors.affiliation: SRI International, Biosciences Division, Menlo Park, CA, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: McFarlane
authors.affiliation: SRI International, Biosciences Division, Menlo Park, CA, USA.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Riccio
authors.affiliation: SRI International, Biosciences Division, Menlo Park, CA, USA.
authors.forename: Rupa
authors.initials: R
authors.lastname: Doppalapudi
authors.affiliation: SRI International, Biosciences Division, Menlo Park, CA, USA.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Mirsalis
authors.affiliation: Tropical Projects, Hitchin, United Kingdom.
authors.forename: R John
authors.initials: RJ
authors.lastname: Horton
authors.affiliation: Veterinary School, San Marcos University, Lima, Peru.
authors.forename: Armando E
authors.initials: AE
authors.lastname: Gonzalez
authors.affiliation: Department of Microbiology, School of Sciences and Center for Global Health-Tumbes, School of Sciences, Universidad Peruana Cayetano Heredia, Lima, Peru Cysticercosis Unit, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.
authors.forename: H Hugo
authors.initials: HH
authors.lastname: Garcia
authors.forename: Robert H
authors.initials: RH
authors.lastname: Gilman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000871:Anthelmintics / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000633:toxicity; D001562:Benzimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000633:toxicity; D002319:Cardiovascular System / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D007940:Leukemia L5178 / Q000235:genetics; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000871:Anthelmintics; D001562:Benzimidazoles; C011030:oxfendazole
keywords: anthelmintic; benzimidazole; cysticercosis; soil-transmitted helminths