Population Pharmacokinetics of Benznidazole in Children With Chagas Disease

Population Pharmacokinetics Study of Benznidazole in Children With Chagas Disease

Background: Chagas disease is a parasitic infection caused by the Trypanosome cruzi. The initial phase of the infection happens mainly in children. Up to 10% of infected children die. Survivors often develop chronic infection leading to heart disease and other complications in 30% of patients. These complications often result in death or severe handicaps in early adulthood, depriving societies of individuals in their most productive years.

There are 20 million people infected in Latin America. Complications lead to 20,000 deaths every year.

Treatment during the acute phase with benznidazole leads to a high cure rate. However, there are very few studies of this drug and virtually none in children, even though benznidazole was developed over 30 years ago.

Hypotheses and Specific Aims: We hypothesize that the pharmacokinetics of benznidazole in children is different from adults, and that obtaining information on how it is absorbed, distributed and eliminated in children will allow optimization of treatment of Chagas disease in this population. This will in turn improve the outlook for children by reducing mortality and long term complications. We aim to study the pharmacokinetics of benznidazole in children receiving the drug for treatment of Chagas disease, and to correlate it with treatment effectiveness and incidence of adverse effects.

Potential Impact: This novel knowledge will allow better and more rational approaches to the treatment of Chagas disease. It will also set the foundation for further studies that will be able to test improved therapies that may increase treatment response in vulnerable children.

Study Overview

• Status: Completed
• Conditions: Chagas Disease
• Intervention / Treatment: Drug: Benznidazole

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1425
    • Parasitology Division, Children's Hospital "R Gutierrez" of Buenos Aires

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 12 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Children 2 - 12 years old of both sexes, with a diagnosis of Chagas' disease and eligible for treatment with benznidazole, as per current treatment protocols.
• Chagas disease diagnostic criteria: At least 2 positive serological tests for Trypanosoma cruzi infection (ELISA, hemoagglutination, particle agglutination tests).
• Informed consent signed by the parents, and consent or assent of the patients (according to age and consenting capacity).

Exclusion Criteria:

• Patients with a history of hypersensitivity to benznidazole or any of the drug excipients
• Immunocompromised patients
• Altered hepatic function (increase in AST/ALT x3 or bilirubin x3) or altered renal function (increase in creatinine x3)
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Benznidazole; Treatment of pediatric Chagas disease with benznidazole	Drug: Benznidazole; benznidazole (RADANIL®, Roche) 5-8 mg/kg/d bid PO for 60 days; Other Names: Children with Chagas Disease Treated with Benznidazole; Niños con Chagas en Tratamiento con Benznidazol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Description of Population pharmacokinetics parameters of benznidazole (i.e. median population clearance, absorption and volume of distribution, and their respective inter-individual variabilities)	2 months (treatment period)

Secondary Outcome Measures

Outcome Measure	Time Frame
Adverse events	2 months (treatment period)

Collaborators and Investigators

• Sponsor: Hospital de Niños R. Gutierrez de Buenos Aires
• Collaborators: The Hospital for Sick Children; Thrasher Research Fund; Universidad Nacional de La Plata; Fundacion Bunge y Born (Argentina); Consejo de Investigacion en Salud Gobierno de Buenos Aires
• Investigators: Study Director: Jaime Altcheh, MD, Parasitology Service, Children's Hospital "R. Gutierrez" of Buenos Aires; Principal Investigator: Facundo Garcia Bournissen, MD, Division of Clinical Pharmacology & Toxicology, Hospital for Sick Children, University of Toronto; Principal Investigator: Norberto Giglio, MD, Epidemiology Service, Children's Hospital "R. Gutierrez" of Buenos Aires; Principal Investigator: Gideon Koren, MD, Division of Clinical Pharmacology &Toxicology, Hospital for Sick Children, University of Toronto; Principal Investigator: Oscar Della Vedova, Universidad Nacional de La Plata; Principal Investigator: Guido Mastrantonio, Facultad de Ciencias Exactas, Universidad Nacional de La Plata

Publications and helpful links

General Publications

• Altcheh J, Moscatelli G, Mastrantonio G, Moroni S, Giglio N, Marson ME, Ballering G, Bisio M, Koren G, Garcia-Bournissen F. Population pharmacokinetic study of benznidazole in pediatric Chagas disease suggests efficacy despite lower plasma concentrations than in adults. PLoS Negl Trop Dis. 2014 May 22;8(5):e2907. doi: 10.1371/journal.pntd.0002907. eCollection 2014 May.

Study record dates

Study Major Dates

• Study Start: April 1, 2007
• Primary Completion (ACTUAL): May 1, 2011
• Study Completion (ACTUAL): May 1, 2011

Study Registration Dates

• First Submitted: June 16, 2008
• First Submitted That Met QC Criteria: June 17, 2008
• First Posted (ESTIMATE): June 18, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): August 1, 2011
• Last Update Submitted That Met QC Criteria: July 29, 2011
• Last Verified: July 1, 2011

More Information

Terms related to this study

• Keywords: Pediatrics; population pharmacokinetics; Chagas disease; pediatric clinical pharmacology; parasitology; benznidazole; neglected diseases
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Trypanosomiasis; Euglenozoa Infections; Chagas Disease; Physiological Effects of Drugs; Anti-Infective Agents; Immunosuppressive Agents; Immunologic Factors; Antiprotozoal Agents; Antiparasitic Agents; Trypanocidal Agents; Benzonidazole
• Other Study ID Numbers: CHAGAS-CHILDREN-POPPK