Population Pharmacokinetics of Benznidazole in Neonates, Infants and Children Using a New Pediatric Formulation

Abstract

Background There is a major need for information on pharmacokinetics (PK) of benznidazole in children with Chagas disease (CD). We present herein the results of a multicentre population PK, safety and efficacy study in children, infants and neonates with CD treated with BZN (100 mg and the 12.5 mg dispersible tablet, developed in a collaboration of DNDi and LAFEPE). Methods 81 children 0-12 years of age were enrolled at 5 pediatric centers in Argentina. Diagnosis of T. cruzi infection was confirmed by direct microscopic examination or at least two positive conventional serologies. Subject enrolment was stratified by age: newborns to 2 years (minimum of 10 newborns) and >2-12 years. BNZ 7.5 mg/kg/d was administered in two daily doses for 60 days. Five blood samples per child were obtained at random times: at Day 0, at 2 – 5 h post-dose; during steady state, one sample at Day 7 and at Day 30; and two samples at 12 – 24 h after final BNZ dose at Day 60. The primary efficacy endpoint was parasitological clearance by qualitative PCR at the end of treatment. Results Forty-one (51%) patients were under 2 years of age (including 14 newborns <1 month of age). Median age at enrolment was 22 months (mean: 43.2; interquartile range (IQR) 7-72 months). The median measured BNZ Cmax was 8.32 mg/L (IQR 5.95 – 11.8; range 1.79 – 19.38). Median observed BNZ Cmin (trough) concentration was 2 mg/L (IQR 1.25 – 3.77; range 0.14 – 7.08). Overall median simulated Css was 6.3 mg/L (IQR 4.7 – 8.5 mg/L). CL/F increased quickly during the first month of postnatal life and reached adult levels after approximately 10 years of age. Negative qPCR was observed at the end of treatment in all 76 patients who completed the treatment. Five patients discontinued treatment (3 due to AEs and 2 due to lack of compliance). Conclusion We observed lower BNZ plasma concentrations in infants and children than those previously reported in adults treated with comparable mg/kg doses. Despite these lower concentrations, pediatric treatment was well tolerated and universally effective, with a high response rate and infrequent, mild AEs.