Translation of oxfendazole from veterinary medicine to human for antiparasitic and anticancer treatments: an integrated in vitro, clinical and computational approach

Whipworm infection, neurocysticercosis, filariasis, echinococcosis, and fascioliasis are neglected tropical diseases infecting more than 1 billion people worldwide. Current first-line antiparasitic drugs for the treatment of these five diseases are the three benzimidazole anthelmintics, namely albendazole, mebendazole and triclabendazole. However, these benzimidazoles suffer from either low efficacy, severe side effect, or emergent drug resistance. Oxfendazole, a benzimidazole antiparasitic drug in veterinary medicine, demonstrated superior efficacy, good safety and favorable and pharmacokinetics (i.e., drug absorption and disposition in the body) compared to mebendazole, albendazole and triclabendazole. The first goal of this project was to facilitate the transition of oxfendazole from veterinary medicine to human for antiparasitic treatment using clinical and computation approaches.

Oxfendazole safety, tolerability, and pharmacokinetics were evaluated in healthy adults in two phase 1 clinical trials: the first-in-human single ascending dose (SAD) trial and the multiple ascending doses (MAD) trial. A rapid and sensitive liquid chromatography-tandem mass spectrometry method was developed to quantify oxfendazole in study participants’ plasma samples. Oxfendazole was well tolerated under all dosing regimens evaluated (single doses from 0.5 to 60 mg/kg, or multiple doses from 3 to 15 mg/kg once daily for 5 days). Hemoglobin concentration, even though decreased slightly following multiple doses, remained in the normal range of most subjects. Oxfendazole pharmacokinetics was characterized by fast oral absorption, low hepatic extraction, and moderate volume of distribution. Following oral administration, oxfendazole underwent negligible urinary excretion and a small fraction of oxfendazole was metabolized to oxfendazole sulfone and fenbendazole. Oxfendazole exposure increased less than dose-proportionally with the increase in dose because oxfendazole absorption was limited by its low solubility. When administered after a high fat meal, oxfendazole was better absorbed resulting in increased exposure. Whether administered in the fed or fasted state, the dose-normalized exposure of oxfendazole in human was higher than that of albendazole and mebendazole, suggesting that better antiparasitic efficacy might be achieved with oxfendazole.

Because oxfendazole has exposure is not dose proportional, to optimize oxfendazole dose regimens in patients, a population pharmacokinetic model was developed to quantitatively characterize the disposition of oxfendazole and its metabolites under following single ascending dose. In addition, a population pharmacokinetic-pharmacodynamic model was built to correlated oxfendazole pharmacokinetics following multiple ascending doses to its side effect on hemoglobin concentration and its antiparasitic efficacy (i.e., probability of target attainment). Predictions using this model suggested that oxfendazole poses little safety concern with regard to hemoglobin concentration. When the prediction was performed in case of whipworm infections and filariasis, it was showed that multiple low doses of oxfendazole might be effective. The developed models and their applications in exposure-safety analyses and exposure-efficacy analyses will be of importance in guiding oxfendazole dose selection and future clinical trial designs.

In addition to its antiparasitic effect, oxfendazole was also investigated for anticancer effect, which was reported of other benzimidazoles, such as mebendazole, albendazole and fenbendazole. High throughput screening was performed for oxfendazole, albendazole sulfoxide, thiabendazole, fenbendazole, mebendazole and albendazole in the mouse glioma cell line, GL261, and human glioblastoma cell line, U87. The screen suggested that albendazole, mebendazole and fenbendazole were the most potent anticancer agents, while oxfendazole anticancer effect was modest, and thiabendazole and albendazole sulfoxide demonstrated no anticancer effect.