Preclinical pharmacokinetic of benznidazole-loeaded interpolyeeltrolyte complexes for improved treatment of Chagas disease.

GARCÍA, MÓNICA C; GUZMÁN, MARÍA L; ZARAZAGA, PILAR; LITTERIO, NICOLAS; OLIVERA, MARÍA E; JIMENEZ KAIRUZ, ALVARO

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Chagas disease, caused by Trypanosoma cruzi, is an important public health problem in Latin America and worldwide. Benznidazole (BZ) is the selected drug for its treatment. However, it shows very low solubility, several side effects and toxicity, which compromise the efficacy and safety. Moreover, the available pharmaceutical dosage forms are immediate release tablets and the treatment is administered 2 or 3 times daily for 60 days. The high frequency of administrations and long-term treatment are issues that contribute to the abandonment of therapy, affecting therapeutic success. In a previous work, we have developed BZ-loaded interpolyelectrolyte complexes (IPEC) based on polymethacrylates (EE-EL-BZ) and polysaccharides (Ch-AA-BZ) that showed controlled release of BZ. These systems would reduce the adverse effects of BZ and/or allow reducing its frequency of administration. Therefore, this work aimed to evaluate the preclinical pharmacokinetics of BZ-loaded IPECs compared to the currently available tablets (Abarax). The studies were performed six healthy adult mixed breed dogs, with a 3×2 cross-over design. Each dog received all orally administrated treatments after three experiments, with a washout period of 15 days. They received 100 mg of BZ by single oral dose of EE-EL-BZ, Ch-AA-BZ or Abarax, with a randomization schedule. BZ quantification was performed in plasma by high performance liquid chromatography validated method. The AUC of BZ-loaded IPECs was higher than reference treatment (p<0.01). The Cmax of Ch-AA-BZ and tmax of both IPECs were higher than Abarax (p<0.05). The ka, t1/2 and MRT were similar for all the treatments evaluated. Our results indicate that bioavailability of BZ was adequate in the administration of both IPECs. The pharmacokinetic parameters demonstrated that the BZ-loaded IPECs prolonged drug release and provided an increase in the maintenance of drug concentration in vivo, which would allow reducing the frequency of administration.