Population Pharmacokinetics Study of Benznidazole in Children With Chagas'Disease
Condition: Chagas' Disease
MeSH terms: Chagas Disease
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to describe the population pharmacokinetics parameters of
      benznidazole in children with acute or early chronic indeterminate form of Chagas Disease.
    

Detailed description: 
      Treatment of Chagas disease (CD) has been always focused on pediatric population. Initially,
      treatment was recommended only to acute and congenital cases (including newborns diagnosed at
      birth), with good parasitological response of 60% to 85% of patients in the acute phase and
      more than 90% of congenitally infected infants treated in the first year of life.

      Despite existing treatment recommendations for children with CD (from birth to 12y), there is
      no formulation available that meets the needs of target pediatric population, especially the
      younger age groups. Benznidazole (Bz), developed over 30 years ago and the main drug of
      choice, is only available in an 'adult' tablet strength of 100 mg (LAFEPE Benznidazol®).

      With the lack of pediatric formulation, the 100mg tablet needs to be fractionated in ½ and ¼
      tablets or prepared as extemporaneous formulations (macerated, diluted, suspension, etc) to
      adjust the dose to patient weight, often leading to sub or over-dosing, which may affect
      safety and efficacy of the treatment. With regards to children, there is an absolute lack of
      information on Bz PK in the pediatric population and its relationship with treatment safety
      and efficacy.

      In order to respond to the need of a age-adapted, easy to use pediatric formulation, DNDi and
      LAFEPE have joined efforts to develop a 12.5 mg dispersible Bz tablet targeting treatment of
      CD in children < 20 Kg. Once this formulation is available, two pharmacokinetics studies are
      planned to be conducted: a comparative bioavailability study in adult healthy normal
      volunteers and a population pharmacokinetics study in young children.

      The group of newborns, from birth to - 2 years-old children, has been included as they
      represent the population of congenital cases. Current estimates of positive serology for CD
      in women at reproductive age vary considerably from country-to-country ranging from 5-40%,
      with vertical transmission rates of up to 12%. There is consensus that congenital infection
      may remain an important mode of transmission for another generation, and appropriate
      treatment targeting newborns is a possible control strategy (with very high chances of cure)
      with the new pediatric formulation.

      Children 2-12 years-old have also been included as a target population, to represent those
      who may have been infected via congenital or vector-borne transmission, and usually present
      with the early chronic indeterminate form of the disease. In CD endemic countries these
      groups of children are usually diagnosed through school or community screening programs, and
      also have a high chance of cure (> 60-75%) with Bz treatment.

      Population PK has been chosen as the study design as it would minimise the number of samples
      per patient, an important requirement for studies conducted in the pediatric population. The
      dearth of PK data in adults and lack of information on the variability in the target
      population does not allow for power calculations and the use of optimal sampling design for
      definition of the timing of samples. Experts reviewed the available information and
      recommended sparse sampling, with 5 PK samples distributed over the absorption phase (1
      sample), steady-state (2 samples) and elimination phase (2 samples). With a total of 5 PK
      measurements per patient and a total of 80 patients stratified by age, it is expected that PK
      curves and variability can be drawn with an adequate level of precision.

      PK data obtained from this study is expected to inform an age-adapted Bz regimen for the
      pediatric population affected by CD.
    

Intervention name(s): Benznidazole 12,5mg or 100mg
Intervention type(s): Drug
Intervention description(s): All 80 subjects recruited into the study will receive treatment with:
- Benznidazole (Laboratório Farmacêutico do Estado de Pernambuco -LAFEPE - Recife - Brazil; tablet 12.5mg or 100mg), 7.5 mg/Kg/day PO (actual range of 5.5-8.5 mg/Kg/d), divided in two daily doses, for 60 days.
Other intervention name(s): BNZ
Intervention MeSH terms: Benzonidazole
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Chagas Disease; Trypanosoma Cruzi; T.Cruzi