Improving the in vitro dissolution rate and pharmacokinetic performance of fenbendazole in sheep using drug nanocrystals

Benzimidazole methylcarbamate anthelmintics, including fenbendazole (FBZ), have only limited water solubility and small differences in drug solubility may have a major influence on their absorption, pharmacokinetic behavior and anthelmintic efficacy. To improve FBZ water solubility and dissolution rate, novel self-dispersible nanocrystals (SDNCs) of FBZ were recently described. In this work, the pharmacokinetic behavior of the SDNCs of FBZ and Poloxamer 188 was compared against a physical mixture (PM) of its components. The experiment was conducted following a crossover design with two different experimental phases. In phase I, sheep were treated with the SDNC (n = 3) or the PM (n = 3) formulations by the intraruminal route at the same dose rate (5 mg/kg). The treatment groups were reversed after a 7-days washout period. A non-compartmental analysis of the concentration in plasma versus time results showed that the calculated Cmax and AUC(0-T) were significantly higher (p < 0.05) for FBZ and its metabolites after the SDNC treatment compared to the PM (for FBZ: Cmax 0.346 mu g/mL and AUC(0-T) 10.1 mu g.h/mL after the SDNC vs Cmax 0.157 mu g/mL and AUC(0-T) 5.1 mu g.h/mL after the PM treatment). Additionally, population pharmacokinetic parameters of FBZ were estimated for the first time in sheep. In conclusion, the formulation of FBZ as SDNCs is a promising approach to improve FBZ dissolution reaching a higher drug plasma exposure in ruminants.

Automated summary

The pharmacokinetic behavior of self-dispersible nanocrystals (SDNCs) of the anthelmintic fenbendazole (FBZ) was compared to a physical mixture (PM) of its components in sheep. Results showed that the SDNCs treatment resulted in significantly higher plasma concentrations and exposure of FBZ and its metabolites compared to the PM treatment.