eers (TABLE 6).
Table 6: Summary of Benznidazole Pharmacokinetic (PK) Parameters Following a Single Oral Dose of 100 mg Benznidazole Administered Under Fasting Conditions in Adult Healthy Volunteers
a Tmax is presented as median (range)
Preparations for 100 mg Benznidazole Oral Dose
One Benznidazole 100 mg Tablets Taken Whole
Slurry prepared with one Benznidazole 100 mg Tablet
Slurry prepared with eight Benznidazole12.5 mg Tablets
Parameter
Mean (SD)
Mean (SD)
Mean (SD)
Cmax (mg/L)
2.4 (0.5)
2.4 (0.4)
2.4 (0.4)
Tmaxa (h)
2 (1 – 4)
2 (0.5 – 4)
2 (1 – 4.5)
AUC (mg*h/L)
43.5 (9.0)
41.8 (9.6)
44.1 (11.8)
Effect of Food
Benznidazole Cmax and AUC were not affected by the administration of Benznidazole 100 mg tablet with a high-fat, high-caloric meal (approximately 1034 total kcal, 67 kcal from fat, 42 kcal from carbohydrates, 59 kcal from protein) compared with fasted conditions in adult healthy volunteers. Serum concentrations of benznidazole reached peak levels at 3.2 hours (1-10 hours) after administration of Benznidazole Tablets 100 mg tablet after a high-fat, high-caloric meal, and at 2.0 hours (0.5-4 hours) in fasted conditions [see Dosage and Administration (2.1)].
Distribution
Protein binding is reported to be approximately 44 to 60 %.
Elimination
The elimination half-life on benznidazole is approximately 13 hours in healthy volunteers following single dose.
Metabolism
Benznidazole metabolism pathway is unknown.
Excretion
Benznidazole and unknown metabolites are reported to be excreted in the urine and feces.
Specific Populations
The effect of sex, race, renal impairment, or hepatic impairment on the pharmacokinetics of benznidazole is unknown.
Drug Interaction Studies
In vitro studies showed that benznidazole is a P-gp substrate and does not notably induce Cytochrome P450 enzymes 1A2, 2B6, and 3A4 at concentrations up to 100 uM.
12.4 Microbiology
Mechanism of Action
Benznidazole inhibits the synthesis of DNA, RNA, and proteins within the T. cruzi parasite. Studies suggest that benznidazole is reduced by a Type I nitroreductase (NTR) enzyme of T. cruzi producing a series of short-lived intermediates that may promote damage to several macromolecules including DNA. In mammalian cells, however, benznidazole is metabolized by reduction of the nitro group to an amino group by a Type II NTR enzyme. The precise mechanism of action is not known.
Antimicrobial Activity
Benznidazole is active against all three stages, trypomastigotes, amastigotes, and epimastigotes, of T. cruzi. However, the sensitivity of T. cruzi strains to benznidazole, from different geographic regions, may vary.
Resistance
Studies in vitro and in mice infected with T. cruzi suggest a potential for development of resistance to benznidazole.
The mechanisms of drug resistance appear to be multifactorial. These mechanisms include decreased activity due to a mutation in the nitroreductase (TcNTR) gene. Other mechanisms include higher efflux activity due to over expression of TcPGP1 and TcPGP2 genes that encode p-glycoprotein as well as TcABCG1 genes that encode ATP-binding cassette transporters. Also, some studies reported overexpression of other genes TcFeSOD-A and TcCyP19 that encode superoxide dismutase and cyclophilin, respectively, which have diverse biological function and may help parasite survival. However, the clinical re |
