Improving the in vitro dissolution rate and pharmacokinetic performance of fenbendazole in sheep using drug nanocrystals. (January 2022) - Melian, María Elisa
Abstract: 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 AUC0-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 μg/mL and AUC0-T 10.1 μg.h/mL after the SDNC vs Cmax 0.157 μg/mL and AUC0-T 5.1 μg.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. Graphical abstract: Unlabelled Image Highlights: In vitro dissolution of fenbendazole was improved by its formulation as nanocrystal. Nanocrystals of fenbendazole presented an improved bioavailability in sheep. Pharmacokinetic parameters of fenbendazole were estimated in sheep.