Population pharmacokinetic-pharmacodynamic analysis of benznidazole monotherapy and combination therapy with fosravuconazole in chronic Chagas disease (BENDITA)

Abstract

INTRODUCTION: The currently recommended 8-week daily benznidazole regimen for Chagas disease is poorly tolerated. While shorter benznidazole monotherapy and combination regimens have been explored, the pharmacokinetic/pharmacodynamic (PK/PD) relationship remains poorly understood. OBJECTIVES: i) To describe the population pharmacokinetics of benznidazole and assess drug-drug interactions with fosravuconazole in patients with chronic Chagas disease, ii) to explore the relationship between benznidazole exposure and anti-trypanosomal treatment effects. METHODS: This was a secondary analysis based on data from the previously published BENDITA study (NCT03378661), a dose evaluation trial in adults with chronic indeterminate Chagas disease (n = 210). Patients were randomized to placebo, the standard benznidazole dose (300 mg/day for 8 weeks), or lower total dose regimens (300 mg/day for 4 or 2 weeks; 150 mg/day for 4 weeks alone or combined with fosravuconazole 300 mg/week; 300 mg/week for 8 weeks plus fosravuconazole 300 mg/week). Benznidazole pharmacokinetics were evaluated using nonlinear mixed-effects modeling. The relationship between individual benznidazole exposure and the pharmacodynamic (PD) endpoint was explored using beta binomial regression. The PD endpoint (qPCR positivity) was defined as the proportion of qPCR-positive blood samples collected post-treatment over 12 months of follow-up, capturing the frequency of detectable parasitemia per patient. RESULTS: Benznidazole pharmacokinetics were well described by a transit-absorption model with one-compartment disposition. Bioavailability was 13% lower in men than in women, and coadministration of fosravuconazole increased benznidazole clearance by 18% (both effects considered not clinically relevant). In the placebo arm, nearly all patients (97%) remained qPCR positive, with most showing qPCR positivity above 40%. Among patients receiving benznidazole, post-treatment qPCR positivity was substantially lower. In the 2-week arm, three patients had multiple positive qPCR samples (up to 43% PCR positivity). In contrast, individual qPCR positivity in the 4-8-week arms did not exceed 20% (i.e., one or no positive samples), with one non-adherent exception. The PK/PD analysis did not identify a significant pharmacokinetic driver of treatment response. While the study was not powered for between-arm comparisons, the findings suggest that lower total dose regimens (4 weeks daily or 8 weeks weekly) may provide efficacy comparable to the standard 8-week regimen. CONCLUSION: This study supports prior findings that the standard 8-week benznidazole regimen is excessive. Future trials using qPCR in factorial randomized designs should evaluate both treatment duration and dosing to optimize tolerability while maintaining efficacy.