A number of BZ anthelmintics used in veterinary medicine have been considered for transition to human use, including oxibendazole and oxfendazole (OXF). In addition, flubendazole, already approved for use as an intestinal anthelmintic, is also being developed as a treatment against adult filarial worms causing river blindness and elephantiasis in humans. Oxfendazole has long been under preclinical investigation as a potential new treatment for neurocysticercosis and echinococcosis. The initial placebo-controlled study of Taenia solium cysticercosis in pigs (the normal host for larval forms of the cestode) showed that a single high dose of OXF (30 mg/kg) but not praziquantel (PZQ; 50 mg/kg PZQ) could eliminate the encysted larvae as observed in necropsy 10 to 12 weeks after drug administration. A follow-up study demonstrated the dose-dependent cysticidal effects of OXF in several tissues, with no viable cysts being observed at the highest dose of OXF tested, 30 mg/kg. A third study confirmed that cysts do not die immediately, the decrease in viable cysts becoming more pronounced across the 12-week time frame of the study; 12 weeks after the administration of a single dose of OXF, viable cysts had been fully eliminated from muscle, heart, and tongue and fully cleared from the brains of 3 of 4 pigs studied. Importantly, the pharmacokinetic study of OXF disposition in pigs revealed that the metabolic half-life (t1/2) of OXF is long, 21.6 hours, a value comparable to its t1/2 in ruminants.
Although there is considerable experience with BZ anthelmintics, both individually and as a class, many of the available data come from experience postregistration rather than from extensive preclinical testing. Since the original work on most BZ anthelmintics was conducted some 30 to 40 years ago, the toxicological data used for the original approvals are limited, often unpublished, and do not comply with current regulatory standards. The lack of a requirement to update basic toxicological data or to conduct new studies once a compound is approved means that there has been little incentive to undertake new studies and even less to place any data gathered into the public domain. Thus, in order to transition any BZ from animal to human use, it is necessary to fill the current data gaps and to bring the dated toxicology package up to current regulatory standards. Typically, the areas lacking in these earlier toxicological evaluations are genetic toxicology, pharmacokinetics and toxicokinetics (TKs), safety pharmacology, and the species and numbers of animals studied. Using the available published data on OXF, the data from the original toxicology package, and knowledge of BZ class toxicology, a series of OXF studies in rat and dog were devised to provide missing data and to bring the toxicology package up to date in support of an Investigational New Drug application for a First in Human (FIH) study. Toxicokinetic evaluation is also a key component of the present studies, as TK data for OXF have not been available in the public domain.
Earlier work on OXF includes chronic toxicity studies in rat and dog. In those 1-year studies, rat was more sensitive to the adverse effects of OXF than was dog, the no effect dose for rat being 0.7 mg/kg/d and for dog being 13.5 mg/kg/d. Extrapolating (using a body surface area calculation) from the results of those chronic OXF toxicology studies, the most conservative estimate of a no-effect chronic dose for humans (based on an NOEL derived from a 1-year study) is 0.13 mg/kg. A conservative dose of 0.3 mg/kg has been proposed as the starting point for a single dose Phase I OXF study. Furthermore, since the principal toxicology target organs appear to be the bone marrow and liver, safety monitoring for the proposed Phase I study includes clinical chemistry indicators of bone marrow and liver function. Coupled with OXF’s lack of induction of behavioral effects in rat, CV effects in dog or genetic toxicology signals in standard Ames bacterial, mouse lymphoma, or rat micronucleus assays, the results of the present rat pharmacokinetic, TK, toxicology, and safety studies support the investigation of OXF as a potential anthelmintic medication against human helminth species.
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.
Ellen E. Codd, International Journal of Toxicology (2015), 34, (2), 129-137