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

Background Flubendazole, originally developed to treat infections with intestinal nematodes, has been shown to be efficacious in animal models of filarial infections. For treatment of filarial nematodes, systemic exposure is needed. For this purpose, an orally bioavailable amorphous solid dispersion (ASD) formulation of flubendazole was developed. As this formulation results in improved systemic absorption, the pharmacokinetic and toxicological profile of the flubendazole ASD formulation have been assessed to ensure human safety before clinical trials could be initiated. Methods & findings Safety pharmacology, toxicity and genotoxicity studies have been conducted with the flubendazole ASD formulation. In animals, flubendazole has good oral bioavailability from an ASD formulation ranging from 15% in dogs, 27% in rats to more than 100% in jirds. In in vivo toxicity studies with the ASD formulation, high systemic exposure to flubendazole and its main metabolites was reached. Flubendazole, up to high peak plasma concentrations, does not induce C-max related effects in CNS or cardiovascular system. In repeated dose toxicity studies in rats and dogs, flubendazole-induced changes were observed in haematological, lymphoid and gastrointestinal systems and in testes. In dogs, the liver was an additional target organ. Upon treatment cessation, at least partial recovery was observed for these changes in dogs. In rats, the No Observed Adverse Effect Level (NOAEL) was 5 mg (as base)/kg body weight/day (mg eq./kg/day) in males and 2.5 mg eq./kg/day in females. In dogs, the NOAEL was lower than 20 mg eq./kg/day. Regarding genotoxicity, flubendazole was negative in the Ames test, but positive in the in vivo micronucleus test. Conclusions Based on these results, in combination with previously described genotoxicity and reproductive toxicity data and the outcome of the preclinical efficacy studies, it was concluded that no flubendazole treatment regimen can be selected that would provide efficacy in humans at safe exposure. Author summary This article describes pharmacokinetic profiles and results of safety pharmacology, toxicity and genotoxicity studies with an oral ASD formulation of flubendazole with improved bioavailability. Flubendazole administered as ASD formulation has good oral bioavailability in animals ranging from 15% to more than 100%. In in vivo toxicology studies, increased systemic exposure does not induce C-max-related effects in CNS and cardiovascular systems. Increased exposure upon repeated dosing results in changes in haematological, lymphoid and gastrointestinal systems and in testes. In dogs, the liver was an additional target organ. These changes were at least partially reversible. Flubendazole is negative in the Ames test but positive in the in vivo micronucleus test. Because of the carcinogenic risk associated with this positive effect in the in vivo micronucleus test, exposure duration in patients should not exceed one day. Flubendazole-induced toxicity and associated risk is monitorable and controllable in patients if stringent precautions are applied in view of testicular toxicity and previously described teratogenicity. Considering both, treatment regimen needed for efficacy and outcome of toxicity and genotoxicity studies, it was concluded that the risk/benefit associated with the use of orally bioavailable flubendazole for the treatment of onchocerciasis in the field does not support further development.