Drug-Drug Interaction Study of Benznidazole and E1224 in Healthy Male Volunteers.

E1224 is a prodrug of ravuconazole (RVZ), an antifungal drug with promising anti-Trypanosoma cruzi activity, the causative organism of Chagas disease (CD). This study was designed to assess the pharmacokinetics (PK) and safety interactions of benznidazole (BNZ), the drug of choice for treatment of CD, and E1224 in healthy volunteers.This open-label, single-centre, sequential, single and multiple oral dose study enrolled 28 healthy male subjects. These subjects received BNZ (2.5 mg/kg) once daily on Day 1 and Day 9 and twice daily from Day 12 to Day 15, and E1224 once daily from Day 4 to Day 15 (loading dose of 400 mg for 3 days and maintenance dose of 100 mg for 9 days).The maximum concentration (Cmax) and area under the concentration curve from zero to infinity for BNZ were comparable whether BNZ was given alone or with E1224 at steady-state, with the ratios of geometric means for BNZ-RVZ/BNZ of 0.96 and 0.83, and corresponding 90% confidence intervals (CI) of [0.91-1.10] and [0.80-0.87], respectively. However, RVZ Cmax and area under the concentration curve from zero to 24 h increased by about 35% when concomitantly administered with BNZ at steady-state (ratio of geometric means for RVZ-BNZ/RVZ of 1.31 and 1.36, and corresponding 90% CI [1.23-1.39] and [1.31-1.41], respectively). Both compounds were well tolerated. There were no clinically relevant safety interactions between E1224 and BZN. Given these results, co-administration of RVZ and BNZ should not require any adaptation of E1224 dosing.