Population pharmacokinetics and biodistribution of benznidazole in mice

Abstract

Objectives To evaluate the population pharmacokinetics of different benznidazole treatment regimens and the drug’s biodistribution in mice. Methods Two hundred mice were divided into five groups according to benznidazole dosing regimens: (1) 100 mg/kg/day for 20 days; (2) 100 mg/kg/day for 40 days; (3) 200 mg/kg/day for 20 days; (4) 40 mg/kg/day for 20 days; or (5) 40 mg/kg/day for 40 days. The mice were euthanized and blood, heart, liver, colon and brain were collected. Samples were prepared by liquid-liquid extraction and analysed by HPLC-diode-array detection. The pharmacokinetic analysis of benznidazole was evaluated via non-linear mixed-effects modelling using the NONMEN program. Results Our results demonstrate that mouse weight allometrically influences benznidazole clearance; the AUC curve and the highest plasma concentration are dose proportional; benznidazole does not influence its own metabolism; its tissue distribution is limited; and the standard treatment regimen for Chagas’ disease in mice (100 mg/kg/day for 20 days) is inadequate from a pharmacokinetic standpoint, as are the other regimens tested in this study (100 mg/kg/day for 40 days, 200 mg/kg/day for 20 days and 40 mg/kg/day for 20 or 40 days). Conclusions Benznidazole reformulations that allow better tissue penetration and plasma and tissue exposure should be evaluated to enable higher cure rates in both animals and patients. The population pharmacokinetic model developed here can allow optimization of the dosing regimen of benznidazole to treat experimental Chagas’ disease. Determining appropriate treatment regimens in animals allows translation of these to clinical studies.

Treatment With Suboptimal Dose of Benznidazole Mitigates Immune Response Molecular Pathways in Mice With Chronic Chagas Cardiomyopathy

“…However, Bz has considerably reduced efficacy in the chronic phase, and controversial data support or do not support the efficacy of Bz in increasing negative seroconversion therefore interrupting the progression of ongoing CCC (Viotti et al, 2006;Bern, 2011;Machado-de-Assis et al, 2013;Morillo et al, 2015;Rassi et al, 2017). Benznidazole, a nitroimidazole derivative, has been used for CD treatment in the last 70 years, but relevant studies concerning its pharmacokinetics and biodistribution in humans and mice emerged only in the last decade (Soy et al, 2015;Perin et al, 2017;Perin et al, 2020), showing how we still lack information regarding its mechanism of action and triggered pathways. It is known that Bz is a prodrug, which exerts its effect after activation by the type I trypanosomal nitroreductase enzyme, inherent to T. cruzi and other protozoa, thus producing reactive metabolites that have trypanocidal effect in the intracellular and extracellular forms of the parasite (Bern, 2011;Kratz et al, 2018).…”

Benznidazole Treatment: Time- and Dose-Dependence Varies with the Trypanosoma cruzi Strain

“…These finding could be related to the profile of resistance of the VL-10 strain to the BZN. Furthermore, pharmacokinetic studies in mice demonstrate that the BNZ plasma concentration remains within the range considered ideal to eliminate intraand extracellular parasites (3-6 µg/mL) for a short time [27,28], which does not occur in humans [29].…”

Nanomedicines against Chagas disease: a critical review

“…The classification is based on BNZ’s dose number (which for BNZ is 1; dose numbers ≤ 1 correspond to highly soluble drugs) and on its calculated partition coefficient value clogP, a lipophilicity indicator and the most critical parameter predictor of passive membrane permeability (which for BNZ is 0.9; a clogP value below 1.35 is indicative of low permeability) [ 29 , 55 ]. In contrast, others consider BNZ as a class-IV drug, this is, a poorly soluble and poorly permeable molecule [ 30 ] with low tissue distributions in healthy mice [ 56 ].…”