BNZ Pharmacology
Benznidazole is an oral, broad spectrum nitroimidazole antimicrobial
that has activity against bacteria and several parasites. It has
demonstrated efficacy against in vitro T. cruzi strains in
several in vivo animal models 52–56. According to the
Biopharmaceutical Classification System (BCS)57,58 BNZ
belongs to Class IV drugs (reduced solubility and permeability); it is a
liposoluble drug with very low solubility in water, and a weak base at
physiological pH range. BNZ solubility in distilled water or simulated
gastric and enteric fluids is reported between 0.2 mg/ml and 0.4 mg/ml.
According to this, BZN is classified as a low-permeability drug with a
log P of 1.6458.
BZN is considered a prodrug, requiring activation by parasite
nitroreductase enzymes that reduce BZN, initiating a cascade of
reactions leading to the formation of highly reactive drug
metabolites27. The main parasite enzyme involved in
BZN activation is believed to be a type 1 nitroreductase. The resulting
BZN metabolites, such as dialdehyde glyoxal, bind to parasite
macromolecules disrupting T. cruzi metabolism and other vital
functions, and leading to parasite cell death27.
However, using a metabolomics approach to asses BZN mechanism of action,
Trochine et al. proposed that the covalent binding of BZN with low
molecular weight thiols as well as with protein thiols is a primary
cause of the drug’s toxicity against T. cruzi, instead of glyoxal
generation as formerly stated59. This suggests that
BZN acts in a complex manner and there are still some remaining
uncertainties about its mechanisms of action: metabolomic studies are a
promising frontier in this research area.
T cruzi resistance to BZN is not well described in literature.
Some in-vitro studies have reported that some parasite strains have a
‘natural’ in-vitro resistance to BZN associated with overexpression of
ABCG transporter60, but this evidence has been
questioned, as in-vitro results do not correlate with therapeutic
outcomes in humans61. Other studies with in vitro data
suggest that susceptibility of different T.cruzi strains to BZN
fluctuates, but the 50% inhibitory concentration (IC50) values remain
≤19.5 μg/mL (75 μM) and can vary 10-fold within the same assay. Activity
against different forms of the parasite (epimastigotes, trypomastigotes,
or amastigotes) also appears to vary within a relatively small
range62,63, and it should be considered that many
studies are performed on the epimastigote stage, which is easier to
culture but not the human stage of the parasite. Additionally, time-kill
studies indicate that BZN trypanocidal effect is both time and
concentration dependent 62–64. Using multipleT.cruzi strains and a high-throughput screening platform, a rapid
trypanocidal effect was demonstrated with 100% parasite clearance
against multiple divergent T. cruzi genotypes, a rate superior to
that for ergosterol biosynthesis inhibitors63.
After oral administration, BZN is quickly absorbed from the human
intestine (Ka = 1.14/h), with a plasmatic peak within 2–4 hours after
drug intake8,65. The impact of food on absorption has
not been systematically investigated. Some evidence points to first step
elimination by hepatic biotransformation and entero-hepatic
recirculation, possibly with some degree of enteric metabolism as well,
but little research has been conducted in this area. Absolute
bioavailability in humans has never been formally estimated due to the
absence of an intravenous formulation apt for human use, though a mean
relative oral bioavailability of 91.7% in three healthy adults when
comparing liquid to solid oral formulations was
reported66. Steady-state plasma concentrations are
reached within 3 days of initiation of a twice-daily dosing
regimen8,66. BZN distributes widely into tissues,
including the central nervous system (CNS)67,68, with
higher volume of distribution in children compared to
adults8. The drug reaches CNS concentrations close to
70% of those observed in plasma, which has allowed successful treatment
of Chagas CNS infections (e.g. meningoencephalitis) in immunosuppressed
patients69–72. Plasma protein binding of BZN is
approximately 50% and is thus not expected to lead to significant
interactions with other drugs 54.
Clearance of BZN is mainly by biotransformation (>80%)68,73, believed to take place mostly in the liver,
probably by members of the cytochrome P450 (CYP) family and/or tissue
nitro-reductases. However, few studies to date have explored the details
of the metabolic pathways responsible for BZN elimination. Approximately
6–20% of the drug can be found unchanged in urine, with differences
depending on age of the patient (e.g., children seem to eliminate more
unchanged drug in urine compared to adults); and the rest of the drug
has been observed as reduced and conjugated.74
Mean BZN half-life is 13 hours in adults66 and
significantly shorter in children (3 to 6 hours for 2 to 7 year-old
patients and 9 to 10 hours in children 7 to 12 years) as observed in two
prospective clinical trials8. This difference in
clearance and half-life between different age groups implies average
steady-state concentrations of BZN lower in children than in adults.
Interestingly, this difference does not seem to affect the efficacy of
BNZ since in a prospective clinical trial, all treated children showed
good response to treatment despite lower plasma concentrations of the
drug8. When comparing the data obtained in this study
with previously reported adult results66, a
progressive decrease in the clearance rate of BZN with increasing age
was observed (i.e. the older the patient, the slower the drug was
eliminated). The specific mechanisms for drug elimination in children
and adults remain undiscovered. Research in the area is actively testing
different hypotheses such as slower drug metabolism in adults and
impaired drug absorption in younger children. BNZ pharmacokinetics and
treatment response in teenagers and young adults have never been
studied, so the assumption that it would be in between children and
adults is so far unsupported by actual evidence.
The most commonly used BNZ dosing regimen, reported in the majority of
the evidence published to date (see table 1 ) uses doses ranging
from 5 to 8 mg/kg/day orally, in two daily doses for 30 to 60 days. BZN
can also be administered in three daily doses, with a clear tendency in
international guides for recommending 5 rather than 8 mg/kg/day and
twice daily rather than thrice.48
Duration of treatment in children and adults is currently under review
and some expert guides are already recommending shorter
treatments8,75, supported by the fact that treatment
in children is proven to be effective despite differences in PK with
adults leading to lower concentrations and shorter half-lives, without
detectable drop in effectiveness and with less adverse
reactions8,75. A few trials enrolling children who
received 30 days of treatment have showed good
results42,76, and recent evidence points towards
possible efficacy of lower BNZ doses or less frequent dosing for adults
and teenagers too65,77,78. Lower treatment duration
has also proven to be effective in adults in preliminary results of an
unpublished clinical trial (NCT03378661) that showed 89.3% of
therapeutic response (measured as a negative PCR) after a 4 week
treatment compared to 82.8% after 8 week-treatment. There are currently
other ongoing trials addressing BZN dairy doses and duration as well
such as BETTY trial79 and MULTIBENZ (NCT03191162),
that may change treatment regimen in the next few years, assuming that
sustained long term responses are demonstrated.
The most commonly observed adverse drug reactions (ADRs) associated with
BZN use includes rash and pruritus (usually after 7 to 12 days of
treatment), headache, myalgia, and gastrointestinal discomfort (in the
first days of the treatment). Drug-associated hepatitis, leucopenia,
peripheral neuropathy, and severe drug hypersensitivity (Stevens-Johnson
syndrome and other reactions with systemic symptoms) are less frequent.
The median proportion of severe side effects is
2.7%45 and trough BZN serum concentrations did not
appear to be related to the appearance of serious ADRs in a small study
in adults80, evidence for a concentration-adverse
event relationship has been observed in pediatric
studies8,34. A recent prospective study in 99
participants reported some previously unreported ADRs; ten subjects
presented psychiatric symptoms (anxiety, panic attacks, emotional
lability and persecutory delusions), four patients reported sexual
alterations (erectile dysfunction or delay in menstrual cycle with no
alternative explanations) and one patient had a bronchospasm. The
results of this study were in other aspects similar to previously
published literature about BZN adverse reactions.81The safety profile of BZN in children is well described in the
literature; data are consistent and do not suggest any signals of
clinical concern8,34.
The incidence of ADRs between children and adults has not been compared
directly (i.e. in a study enrolling both age groups), but ADRs seem rare
and almost universally mild in younger children, and appear to increase
gradually after 7 years of age in both frequency and severity. It is
very infrequent to observe ADRs in newborns and children under 1 year
old, and rates of treatment discontinuation due to ADRs are
significantly low in children34,47,76,82–85 while
these ranges between 11 and 45% in adult
studies16,45,82,86.
The underlying biological mechanisms for the observed ADRs have not been
studied in depth, but the immune system seems to play an important role,
particularly in the case of cutaneous rashes and hypersensitivity
reactions. This assumption is based on the timing for the moderate
cutaneous reactions (7–12 days after onset of treatment) that mimics
the time course of similar reactions associated to other unrelated
medications known to cause rash (e.g. lamotrigine), and the observation
of rare severe adverse reactions such as Stevens-Johnson syndrome and
drug reactions with eosinophilia and systemic
symptoms83,84. A common immunological trigger for
these reactions and possibly a pharmacogenetic predisposition could
explain these similarities, but studies of potential pharmacogenomic
markers are lacking. Some authors had formerly proposed to associate BZN
with thioctic acid in order to prevent ADRs, based on this compound to
increase hepatic elimination of BZN, but this has proven not to be
effective when evaluated in-vivo.87
BZN has never been formally studied during pregnancy, but it is not
recommended for pregnant women due to the lack of safety data; there is
insufficient information about reproductive safety of this drug, other
than the fact that there have been no reports of malformations or any
other pregnancy complications. However, it should be considered that it
is likely that an unknown number of women were exposed to BZN in the
first trimester by accident and the lack of reports on safety data might
be a good sign so far. Also, there are some reports of treatment during
late-stage pregnancy in emergency situations that did not result in any
complications for the baby and may have saved the mother’s
life69. The main recommendation therefore remains to
avoid BZN during the first trimester of pregnancy and throughout
pregnancy whenever possible until further information becomes available,
though in case of an emergency or a life-threatening situation caused by
CD, we recommend not delaying treatment because of an unproven
teratogenic risk69.
BNZ has been classically contraindicated during lactation, but recent
prospective studies and pharmacokinetic evaluations suggest that the
risk of exposure to BZN from breastmilk for a breastfed baby is
negligible, and lactation should not be considered a contraindication
for CD treatment in those circumstances when treatment cannot be
postponed. 29