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

Abstract

IntroductionChagas disease, caused by the parasite Trypanosoma cruzi, 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.Patients and MethodsProspective 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).ResultsForty 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).DiscussionObserved 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.Trial RegistrationClinicalTrails.gov NCT00699387

Population Pharmacokinetics of Benznidazole in Adult Patients with Chagas Disease

“…Looking deeper into our data set, we noted that only 5.4% of the observed (real) BNZ trough concentrations were below 3 mg/liter; 20% of them were within the optimal range (3 to 6 mg/liter), but most of them (74.54%) were above 6 mg/liter. These results support the views of other authors (26,29) suggesting that standard treatment protocols using BNZ might be significantly overdosing patients and therefore that studies with lower doses in adults might be justified.…”

“…Recently, a study on the population PK of benznidazole in children was published (29), but to our knowledge, the present population PK study is the first to examine benznidazole plasma concentrations in adult subjects with Chagas disease.…”

“…Previous BNZ PK studies were conducted in healthy volunteers (7) or patients with chronic Chagas disease (8) and were analyzed (post hoc analysis) on a population approach basis by Altcheh et al (29). In these studies, combined data from healthy subjects (single dose) and patients (multiple doses) led to a CL/F value of 0.0301 liter/h/kg (2.17 liters/h for a patient of 70 kg) and a typical half-life of 12.77 h. In the present study, performed under steady-state conditions in 39 adults with chronic Chagas disease, the estimated terminal drug half-life was about 36 h, which is quite longer than the previous estimates.…”

Pharmacokinetics of Benznidazole in Healthy Volunteers and Implications in Future Clinical Trials

“…From an opposite point of view, two recent studies based on population pharmacokinetics came to the fore because of a novel hypothesis (5,6). Both studies reach to the conclusion that the benznidazole treatment regimen against Chagas disease in adults might be overdosed.…”

“…Two recent studies performed in Argentina and Spain including pediatric and adult populations, respectively, with Chagas disease used a population pharmacokinetic approach (5,6). One of the main differences regarding population pharmacokinetics is that data are obtained for patients treated with benznidazole, while nonpopulation pharmacokinetic studies are performed with healthy volunteers.…”