Preclinical Studies on the Pharmacokinetics, Safety, and Toxicology of Oxfendazole

Abstract

A two-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 WBC levels, a class effect of benzimidazole anthelminthics, returned to normal during the recovery period. The NOAEL was determined to be >5 but < 25 mg/kg/d and the MTD 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 seven 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.

Oxfendazole mediates macrofilaricidal efficacy against the filarial nematode Litomosoides sigmodontis in vivo and inhibits Onchocerca spec. motility in vitro

“…Furthermore, subacute toxicity, behavioral effects in rats and cardiovascular effects in dogs did not raise safety concerns. These results were reviewed favorably by the FDA and led to further evaluation of oxfendazole in a Phase I trial confirming the safety and pharmacokinetics of single oxfendazole administrations in healthy volunteers [ 20 , 42 ] at doses that are now predicted to mediate macrofilaricidal efficacy. Although results of the multiple ascending dose are not yet published, the design and completion of this study using 3, 7.5 and 15 mg/kg of oxfendazole suggest that dosing for five consecutive days at the predicted human efficacious dose would be possible [ https://clinicaltrials.gov/ct2/show/record/NCT03035760?cond=oxfendazole&rank=2 ].…”

Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Volunteers: a Randomized, Placebo-Controlled First-in-Human Single-Dose Escalation Study

“…These data suggest that dog and pig may represent suitable preclinical models for oxfendazole toxicity and efficacy. In fact, dog has been used especially in cardiovascular safety studies (23), and an extensive pharmacology study has been conducted in Taenia solium cysticercosis in pig (20,21).…”

“…These data suggest that oxfendazole has the potential to be used as an effective treatment for cysticercosis in humans. In addition to the encouraging efficacy data, oxfendazole has shown a favorable safety profile based on safety data accumulated in livestock (22) and, more recently, in a series of formal and comprehensive safety and toxicology studies conducted in dog, rat, and mouse (23). Based on its promising preclinical efficacy and safety profiles, as well as its potentially favorable pharmacokinetic profile in animals, oxfendazole represents an attractive anthelmintic candidate for transition to human use for the treatment of neurocysticercosis and other helminthic infections.…”

Preclinical toxicity and pharmacokinetics of a new orally bioavailable flubendazole formulation and the impact for clinical trials and risk/benefit to patients

“…[8] These organ systems have also been described to be affected by treatment with other benzimidazoles which is in line with their similar mechanism of action (tubulin binding). [9, 10] Dosing with other benzimidazoles like albendazole, mebendazole and oxfendazole in preclinical toxicity studies also resulted in testicular changes. [9, 10] For oxfendazole, the mechanisms underlying the testicular toxicity are most probably disruption of the microtubules, and degeneration of the Sertoli cells.…”