Benznidazole Extended-Release Tablets for Improved Treatment of Chagas Disease: Preclinical Pharmacokinetic Study

Abstract

c Benznidazole (BNZ) is the first-line drug for the treatment of Chagas disease. The drug is available in the form of immediaterelease tablets for 100-mg (adult) and 12.5-mg (pediatric) doses. The drug is administered two or three times daily for 60 days. The high frequency of daily administrations and the long period of treatment are factors that significantly contribute to the abandonment of therapy, affecting therapeutic success. Accordingly, this study aimed to evaluate the preclinical pharmacokinetics of BNZ administered as extended-release tablets (200-mg dose) formulated with different types of polymers (hydroxypropyl methylcellulose K4M and K100M), compared to the tablets currently available. The studies were conducted with rabbits, and BNZ quantification was performed in plasma and urine by ultraperformance liquid chromatography methods previously validated. The bioavailability of BNZ was adequate in the administration of extended-release tablets; however, with the administration of the pediatric tablet, the bioavailability was lower than with other tablets, which showed that the clinical use of this formulation should be monitored. The pharmacokinetic parameters demonstrated that the extended-release tablets prolonged drug release from the pharmaceutical matrix and provided an increase in the maintenance of the drug concentration in vivo, which would allow the frequency of administration to be reduced. Thus, a relative bioavailability study in humans will be planned for implementation of a new product for the treatment of Chagas disease.

Usefulness of real-time PCR during follow-up of patients treated with Benznidazole for chronic Chagas disease: Experience in two referral centers in Barcelona

“…Other factors could explain the treatment's failure. The natural resistance of T. cruzi strains to the two drugs used to treat Chagas disease are known [29], as well as the pharmacokinetics of BZ in organic fluids, which may hinder a correct tissue biodistribution [30][31].…”

Pharmacokinetics and Tissue Distribution of Benznidazole after Oral Administration in Mice

“…Nevertheless, although large amounts of BNZ can reach the heart and colon, as represented by the AUC 0 -6 ratios in relation to plasma, the maximum concentration in plasma may be insufficient for complete parasite elimination in organs during the chronic phase of T. cruzi infection. Recently, the improvement of Chagas disease chemotherapy has been experimentally evaluated with new formulations of BNZ, such as extended-release tablets, solid dispersions, microparticles, and nanoparticles, to increase the maintenance of the drug concentration in vivo (38)(39)(40).…”

Development and characterization of benznidazole nano- and microparticles: A new tool for pediatric treatment of Chagas disease?

“…Later, as a result of an alliance between the Drugs for Neglected Diseases initiative (DNDi) and LAFEPE, a pediatric dosage form (BNZ 12.5 mg tablets) was developed and a corresponding clinical trial (ClinicalTrials.gov Identifier: NCT01549236) was conducted in children weighing <20 kg. This pediatric formulation was registered in Brazil and in 2013 was included on the WHO's Essential Medicines List for children as a new dosage form indicated for children below 2 years old with Chagas disease [5,29,30]. However, in many occasions the pediatric population is still treated by fractioning those tablets according to the body weight of each patient.…”

“…In particular, it is highly effective during the acute phase of the infection and in chronically infected children [4]. Moreover, BNZ treatment is recommended in congenital cases and reactive infections among all children and for patients up to 18 years old in the indeterminate chronic phase [5]. It is worth noting that, recently, BNZ was approved by FDA to treat patients 2-12 ages [6].…”