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. 2023 May 31;17(5):e0010850.
doi: 10.1371/journal.pntd.0010850. eCollection 2023 May.

Population pharmacokinetics of benznidazole in neonates, infants and children using a new pediatric formulation

Jaime Altcheh  1   2   3 , Guillermo Moscatelli  1   2   3 , Martin Caruso  2   4 , Samanta Moroni  1   2   3 , Margarita Bisio  1   2   3 , Maria Rosa Miranda  2   4 , Celia Monla  2   5 , Maria Vaina  2   5 , Maria Valdez  2   5 , Lucrecia Moran  2   6 , Teresa Ramirez  2 , Oscar Ledesma Patiño  2   6 , Adelina Riarte  2   7 , Nicolas Gonzalez  1   2   3 , Jayme Fernandes  8 , Fabiana Alves  9 , Isabela Ribeiro  9 , Facundo Garcia-Bournissen  1   2   10
Affiliations

Population pharmacokinetics of benznidazole in neonates, infants and children using a new pediatric formulation

Jaime Altcheh et al. PLoS Negl Trop Dis. .

Abstract

Background: There is a major need for information on pharmacokinetics (PK) of benznidazole (BNZ) in children with Chagas disease (CD). We conducted a multicentre population PK, safety and efficacy study in children, infants and neonates with CD treated with BNZ (formulated in 100 mg tablets or 12.5 mg dispersible tablets, developed by the pharmaceutical company LAFEPE, in a collaboration with DNDi).

Methods: 81 children 0-12 years old 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 serological tests. 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 within pre-defined time windows 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.

Trial registration: Registered in clinicaltrials.gov #NCT01549236.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Population predicted (PRED) vs Observed (DV) benznidazole concentrations (mg/L).
Fig 2
Fig 2. Individual predicted (IPRED) vs Observed (DV) benznidazole concentrations (mg/L).
Fig 3
Fig 3. Visual Predicted Check (VPC) plot, 1 compartment model with oral absorption, final model with covariates.
Fig 4
Fig 4. Clearance (CL/F) vs Age (years).
CL/F increases rapidly during the first year of life, and reaches the reported adult level approximately at 10 years of age (filled circles: individual estimates for CL/F; lines: median and CI5% and CI95% for CL/F).
Fig 5
Fig 5. Weight-corrected CL/F, showing decrease with age (filled circles: individual estimates for weight-corrected CL/F; lines: median and CI5% and CI95% for CL/F).
See this image and copyright information in PMC

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