Preclinical pharmacokinetics of benznidazole-loaded interpolyelectrolyte complex-based delivery systems.

ABSTRACT

Benznidazole (BZ), first-line drug for Chagas treatment, is available as immediate-release tablets. High frequency of administration, long-term therapy, and side effects of BZ conspire against treatment adherence, and negatively impact in therapeutic success. We have developed BZ-loaded interpolyelectrolyte complexes (IPECs) composed of polymethacrylates (EE-EL-BZ) or polysaccharides (Ch-AA-BZ) for controlled BZ release. This work aimed to evaluate their preclinical pharmacokinetics compared to Abarax® (reference treatment) and to correlate them with the in vitro BZ release. A randomization schedule with a 3 × 2 cross-over design was used. Each healthy dog received a single oral dose of 100 mg of BZ from EE-EL-BZ, Ch-AA-BZ or Abarax®. BZ quantification was performed in plasma by a validated HPLC-UV method. Moreover, in silico simulations using the pharmacokinetic software PK Solutions 2.0™ were calculated for the multiple-dose administration at two dose regimens 100 mg of BZ administered every 12 and 24 h. Also, the relationship between in vitro dissolution and in vivo plasma BZ concentration profiles in a single step was model for IVIVC analysis. BZ was rapidly absorbed from all formulations. The Cmax value for Ch-AA-BZ was 32% higher than reference (p < 0.05) and an earlier Tmax (4.2 h) was observed as compared to EE-EL-BZ (6.0 h). For both IPECs, the Tmax values were higher (p < 0.05) and the areas under the curve were 25% greater than those of Abarax® (p < 0.01). Despite these variations in pharmacokinetics parameters, simulations of once or twice daily dosing showed that all formulations reached a steady-state range concentration above of the minimum therapeutic dose while avoiding high BZ concentrations related to increased side effects. A linear level A IVIVC model was established using plasma concentration profiles and dissolved data obtained. Thus, BZ-loaded IPECs prolonged drug release and formulated as capsules showed improved in vivo performance, in terms of bioavailability and Tmax values, which were significantly higher compared to Abarax®. These BZ carrier systems would be useful for oral administration in the treatment of Chagas disease.