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:…
How strong is the evidence?
Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design. Reported size: 210 participants or records.
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