Chagas' Disease Clinical Trial
Official title:
Population Pharmacokinetics Study of Benznidazole in Children With Chagas'Disease
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.
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.
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