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Population pharmacokinetics of benznidazole in neonates, infants and children using a new pediatric formulation
Jaime Altcheh1,2,3, Guillermo Moscatelli1,2,3, Martin Caruso2,4
1Servicio de Parasitologia y Chagas, Hospital de Niños "Dr Ricardo Gutierrez", Buenos Aires, Argentina.
Insights
This study found that benznidazole (BNZ) treatment for Chagas disease (CD) in children, including neonates, was safe and effective. Despite lower plasma concentrations than adults, BNZ achieved parasitological clearance in all participants who completed treatment.
Area of Science:
- Pediatric Pharmacology
- Infectious Diseases
- Chagas Disease Treatment
Background:
- Significant need for pharmacokinetic (PK) data of benznidazole (BNZ) in pediatric Chagas disease (CD) patients.
- A multicenter study investigated BNZ PK, safety, and efficacy in children, infants, and neonates with CD.
- BNZ was administered in 100 mg tablets or 12.5 mg dispersible tablets.
Purpose of the Study:
- To determine the population pharmacokinetics of benznidazole in pediatric patients with Chagas disease.
- To evaluate the safety and efficacy of benznidazole treatment in children, infants, and neonates.
- To provide essential PK data for optimizing BNZ dosing in pediatric populations.
Main Methods:
- 81 children aged 0-12 years were enrolled across 5 pediatric centers in Argentina.
- BNZ at 7.5 mg/kg/d was given for 60 days, with blood samples collected at multiple time points.
- Parasitological clearance was assessed by qualitative PCR at the end of treatment.
Main Results:
- Lower median BNZ Cmax (8.32 mg/L) and Cmin (2 mg/L) were observed in children compared to adults.
- Simulated steady-state concentration (Css) was 6.3 mg/L.
- All 76 patients who completed treatment achieved negative PCR, indicating universal efficacy.
- CL/F increased with age, reaching adult levels around 10 years.
Conclusions:
- Pediatric treatment with BNZ was well-tolerated with infrequent, mild adverse events.
- Despite lower plasma concentrations, BNZ demonstrated high efficacy in children with Chagas disease.
- The study provides crucial PK and efficacy data for benznidazole in pediatric CD treatment.
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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