Population Pharmacokinetics Study of Benznidazole in Children With Chagas'Disease (Pop PK Chagas)

• Pharmacokinetics Endpoints [ Time Frame: Day 60 ] [ Designated as safety issue: Yes ]

  Plasma level concentrations of benznidazol determined in children at first day of treatment (Day 0), steady state phase (D7 and Day 30) and at the end of treatment (Day 60).

  Population pharmacokinetics parameters of benznidazole in children, including CL, Vd, and Ka.

  Individual AUC.

  Individual Cmax.

  Individual Cmin.

  Individual t1/2 will be estimated using population parameters.

  
  

• Efficacy Endpoints [ Time Frame: Day 60 ] [ Designated as safety issue: No ]
  Parasitological cure rate as determined by qualitative PCR at the end of treatment (Day 60).
  
  
• Safety endpoints [ Time Frame: Day 60 ] [ Designated as safety issue: Yes ]
  Rate of Serious of Adverse Events and/or adverse events leading to treatment discontinuation.
  
  
• Safety Endpoints [ Time Frame: Day 60 ] [ Designated as safety issue: No ]

  Rate and severity of adverse events.

  Covariates to be evaluated: age, gender, weight, height, parasite load at baseline and phase of disease (acute vs chronic).

  
  

Drug: Benznidazole 12,5mg or 100mg

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 Name: BNZ

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.