Population Pharmacokinetic Study of Benznidazole in Pediatric Chagas Disease Suggests Efficacy despite Lower Plasma Concentrations than in Adults

<div><p>Introduction</p><p>Chagas disease, caused by the parasite <i>Trypanosoma cruzi</i>, can lead to long term cardiac morbidity. Treatment of children with benznidazole is effective, but no pediatric pharmacokinetics data are available and clinical pharmacology information on the drug is scarce.</p><p>Patients and Methods</p><p>Prospective population pharmacokinetic (PK) cohort study in children 2–12 years old with Chagas disease treated with oral benznidazole 5–8 mg/kg/day BID for 60 days. (clinicaltrials.gov #NCT00699387).</p><p>Results</p><p>Forty children were enrolled in the study. Mean age was 7.3 years. A total of 117 samples were obtained from 38 patients for PK analysis. A one compartment model best fit the data. Weight-corrected clearance rate (CL/F) showed a good correlation with age, with younger patients having a significantly higher CL/F than older children and adults. Simulated median steady-state benznidazole concentrations, based on model parameters, were lower for children in our study than for adults and lowest for children under 7 years of age. Treatment was efficacious in the 37 patients who completed the treatment course, and well tolerated, with few, and mild, adverse drug reactions (ADRs).</p><p>Discussion</p><p>Observed benznidazole plasma concentrations in children were markedly lower than those previously reported in adults (treated with comparable mg/kg doses), possibly due to a higher CL/F in smaller children. These lower blood concentrations were nevertheless associated to a high therapeutic response in our cohort. Unlike adults, children have few adverse reactions to the drug, suggesting that there may be a direct correlation between drug concentrations and incidence of ADRs. Our results suggest that studies with lower doses in adults may be warranted.</p><p>Trial Registration</p><p>ClinicalTrails.gov <a href="http://clinicaltrials.gov/show/NCT00699387" target="_blank">NCT00699387</a></p>