Development of Flubendazole as a Macrofilaricide Compound. Systemic Exposure in Pigs Treated with Different Formulations.

CEBALLOS, L.; ALVAREZ, L.; MORENO, L.; MACKENZIE, CH.; GEARY, T.; LANUSSE. C.

Amsterdam

Congreso; 12th International Congress of the European Association for Veterinary Pharmacology and Toxicology; 2012

European Association of Veterinary Pharmacology and Toxicology

Introduction: In spite of the well established ivermectin activity against microfilaria, the success of human filariasis control programs requires the use of a macrofilaricide compound. Different in vivo trials suggest that flubendazole (FLBZ), a benzimidazole anthelmintic compound, is a highly efficacious and potent macrofilaricide (1). However, since serious injection site reactions were reported in humans after the subcutaneous FLBZ administration, the search for alternative pharmaceutical strategies to improve the systemic availability of FLBZ has acquired special relevance both in human and veterinary medicine. The goal of the current work was to compare the systemic exposure of FLBZ formulated as either an aqueous hydroxypropyl-β-cyclodextrin solution (FLBZ-HPBCD), an aqueous carboxymethyl cellulose suspension (FLBZ-CMC) or a Tween80-based formulation in pigs. Materials and Methods: Pigs were allocated into three groups (n= 8 each) and treated (2 mg/kg) with FLBZ formulated as either a HPBCD-solution (oral administration), CMC-suspension (oral administration) or Tween80 based-formulation (subcutaneous injection). Blood samples were collected at different times over 54 h post treatment. Plasma samples were analyzed by HPLC. The estimated kinetic parameters were statistically compared by a non-parametric test. Results: Only trace amounts of FLBZ parent drug and its reduced metabolite (R-FLBZ) were measured after administration of the different FLBZ formulations in pigs. The hydrolyzed flubendazole (H-FLBZ) metabolite was the main analyte recovered in the bloodstream in pigs treated with the three experimental FLBZ formulations. The oral administration of the HPBCD-solution accounted for significantly higher (P< 0.05) Cmax and AUC (23.2 ± 4.4 µg.h/mL) values for the main metabolite (H-FLBZ), compared to those observed for the oral CMC-suspension (AUC: 3.5 ± 1.1 µg.h/mL) and injectable Tween80-based formulation (AUC: 7.2 ± 1.7 µg.h/mL). The oral administration of the HPBCD-solution significantly improve the poor absorption pattern observed after the oral administration of the FLBZ-CMC suspension or the subcutaneous injection of the Tween80 FLBZ formulation to pigs. Conclusion: Overall, the work reported here indicates that FLBZ pharmacokinetic behavior can be markedly improved by changes on drug formulation. The advantageous systemic exposure obtained with the cyclodextrin-based formulation may have a great impact in clinical efficacy. This knowledge on a formulation-influenced pharmacokinetic behavior may contribute to the development of FLBZ as a macrofilaricide. References 1. Mackenzie C., Geary T. 2011. Flubendazole: a candidate macrofilaricide for lymphatic filariasis and onchocerciasis field programs. Expert Review Anti Infective Therapy; 5:497-501.