Benznidazole pharmacokinetics in patients with chronic Chagas disease: association with demographic factors and adverse drug reactions

Background The knowledge about benznidazole pharmacokinetics (PK) in patients with chronic Chagas disease (CD) is limited. Objective To evaluate the benznidazole PK parameters in patients with chronic CD, stratified by age, sex, and adverse drug reactions (ADRs) occurrence. Methods Single-centre, open-label, clinical trial that included adult patients with chronic CD who received benznidazole 300 mg/day for 60–80 days. Blood samples were collected on Days 1, 7, 15, 30, and 60 of treatment. Benznidazole was quantified by HPLC-MS/MS and PK analysis used non-compartmental analysis. Results Twenty-nine participants (16 females; 55.2%) were included. Five (17.2%) participants interrupted the treatment definitely due to ADRs. PK parameters after a single benznidazole dose were as follows: Cmax = 2.48(0.53) µg/mL, AUC0–6 = 10.80(2.59) h*µg/mL, and Tmax = 2.7(1.3) h. The steady-state PK parameters on Day 15 were as follows: Cmax,ss = 7.86(2.06) µg/mL, AUC0–6,ss = 42.05(10.87) h*µg/mL, and Tmax,ss = 2.3 (1.2 h). Tmax was longer among those ≥60 years old (P = 0.045), and Cmax (P = 0.0004) and AUC0–6 (P = 0.003) were higher in females, but PK parameters normalized by weight were similar between sexes. The most frequent ADRs were skin reactions (44.8%), gastrointestinal (37.9%), haematological (20.7%), and neurological (27.6%). Sex was associated with gastrointestinal ADRs, while weight was associated with skin reactions. Higher benznidazole plasma levels on Days 1, 7, and 15 of treatment were associated with skin reactions even adjusting for age and sex. Conclusions Benznidazole PK presented little variation according to sex and age, but differences in sex appeared linked to females lower weight. Higher benznidazole plasma levels were associated with skin reactions, indicating a potential dose-dependent relationship of this ADR. Trial registration This study was registered on the Brazilian Clinical Trials Database—REBEC (RBR-5vg8p36). Registered on 11 August 2021. https://ensaiosclinicos.gov.br/rg/RBR-5vg8p36.