Influence of Chagas Disease on the Pharmacokinetics of Benznidazole in the Dog Model

The high variability in efficacy and safety of antichagasic chemotherapy involving benznidazole (BNZ) may be due to pharmacokinetic-related factors. The study evaluated the impact of experimental acute and chronic infections by the Berenice-78 strain of Trypanosoma cruzi on the pharmacokinetics of BNZ in dogs. Twenty-seven mongrel dogs were divided into the following groups: acute infection state treated with BNZ, chronic infection state treated with BNZ, acute and chronic positive controls (not treated with BNZ), and a healthy group treated with BNZ. They were evaluated at (1) basal state, (2) during infection without treatment, for cytokines panel (IL-6, interferon γ (IFN-γ), IL-10 and tumor necrosis factor α (TNF-α)) evaluation, and (3) during BNZ steady-state levels at 10, 30, 40, and 60 days after start of treatment with oral BNZ 3.5 mg/kg b.i.d. administration, in acute and chronic T. cruzi-infection, for BNZ pharmacokinetics and cytokines panel evaluation, and (4) 30 days after BNZ treatment end for cytokines evaluation. BNZ levels in serum samples were quantified using a curve range of 0.1–100 μg/mL in plasma by high-performance liquid chromatography with diode array detection (HPLC-DAD) analysis. Pharmacokinetic parameters remained stable during treatment phases, indicating no autoinduction or inhibition. Acute infection pharmacokinetics resembled that of healthy controls. Chronic infection significantly increased Cmax, Css, and AUC0–12, while decreasing Vd/F and CL/F compared to both healthy and acute groups. Notably, IL-6 levels were elevated ∼7-fold during chronic infection. These data suggest that chronic inflammatory status modulates BNZ disposition, likely via IL-6 mediated P-glycoprotein inhibition. Understanding these pharmacokinetic changes is critical for optimizing BNZ dosing strategies in Chagas disease management.