In an expert consultation meeting held by DNDi in October 2006, consensus was reached for the development of a dispersible tablet formulation of benznidazole for paediatric patients.

To determine the appropriate paediatric tablet strength, the target paediatric therapeutic dose range for benznidazole was defined through a review of available paediatric dose recommendations from the WHO guidelines, national control programmes, and medical literature (Table 1).



The doses below were chosen based on efficacy/safety data in the observed age groups

Table 1: Benznidazole dose recommendations for Chagas infections

Source

Age group

WHO – Chagas Control Technical Expert Group

Congenital infections: 5-10 mg/kg/d

WHO – model prescribing information

Children 12 years old: 5-7 mg/kg/d,
children <12 years old: 10 mg/kg/d (no range provided)

Hoffman-La Roche package insert

Children 12 years old: 5-7 mg/kg/d,
children <12 years old 10 mg/kg/d (no range provided)

Roche, Radanil® insert package

5-8 mg/kg/d bid PO for 60 d

Roche, Rochagan® insert package

5-7 mg/kg/d bid PO for 30-60 d

Children <12 years old, especially with acute disease: up to 10 mg/kg/d for the initial 10-20 days of treatment

Brazilian Ministry of Health, Secretaria de Vigilância em Saúde

Adults: 5 mg/kg/d, children: 5-10 mg/kg/d

2 or 3 times/day PO for 60 d

Brazilian Ministry of Health, Secretaria de Vigilância em Saúde

Acute phase, congenital infection, immunocompromised patients and transplants: 8 mg/kg/d bid PO for 60 d

Consejo de Enfermedad de Chagas Mazza de la Sociedad Argentina de Cardiología

5 mg/kg/day for 30-60 d

 

Considering the target age group of infants under one year of age, for which dose accuracy represents the main challenge and an ideal regimen of a single tablet/intake (maximum of 2 tablets/day), with a single split, the 12.5 mg strength was the most appropriate, allowing coverage of a wide range of infant age and weight.

Studies comparing the recommended doses and  the dose range used in practice show that a significant proportion of children are being over-dosed, especially the patients under 1 year of age, supporting the conclusions of the highest medical need for a paediatric formulation among the infant population.

Clinical experts then discussed the optimal type of drug formulation. While liquid/syrup formulations allow more accurate dosing and do not need dilution before intake, the production of a tablet is easier and is advantageous in terms of packaging, storage, and distribution costs. Dispersible tablets have advantages of both liquids and standard tablets. They allow the use of a minimal amount of non-toxic excipients, can be easily produced, are stable, low cost, and allow for a convenient, easy, and reliable administration in a treatment course of prolonged duration, administered at home.