Nifurtimox Clinical Pharmacology
Many aspects of NF clinical pharmacology are similar to those of BZN.
There is also considerable lack of knowledge on many aspects of its PK,
effectiveness, and metabolism. However, NF is currently undergoing
extensive redevelopment, with some clinical trials already completed and
others in process (NCT04274101) (see table 1 ).
NF mechanism of action is believed to be the generation of nitro-anion
radicals, after activation by parasite nitroreductases in the presence
of oxygen. This leads to production of free radicals that damage vitalT. cruzi cell components, block DNA synthesis and accelerate DNA
and RNA degradation88,89.
Similarly to BZN, NF is hydrophobic, highly liposoluble and distributes
widely to tissues, including the central nervous
system90, a useful property for the treatment of T.
cruzi CNS infections. It has a rapid absorption from gut (Ka 0.77/h),
but undergoes extensive first-pass elimination (much higher than BZN),
leading to only a small fraction of orally administered NF reaching
systemic circulation91,92. NF is administered orally
and reaches peak plasma concentrations after 2 to 4
hours32,90,93 with a relatively short half-life
(approximately 3 hours in adults, and similar in children based on very
limited data)94,95. Liver elimination accounts for
virtually all NF clearance (i.e., unchanged NF elimination in urine is
less than 1% of the administered dose).96
According to a recent trial that reported biopharmaceutical
characteristics after oral administration of 30 mg and 120 mg
tablets96, total systemic exposure to NF was
approximately 71% greater after food than in a fasted state. Mean
(%CV) NF AUC estimates ranged between 1676-2670 µg∙h/L (19–32%) and
Cmax estimates ranged between 425-568 µg/L (26–50%) following
administration of single dose 120 mg NF with food in adult CD patients.
The median time to reach maximum concentration (Tmax) of NF under fed
conditions was 4 hours (range: 2 to 8 hours). Interestingly, in this
study Cmax increased 68%, AUC increased 71%, and Tmax increased by 1
hour after a high-fat meal compared to fasted
conditions.96
Animal liver experiments of NF metabolism have suggested a number of
metabolites97, but this aspect has only been studied
in a limited number of humans, with preliminary confirmation of the
metabolites observed in animal experiments and further observation of a
range of minor metabolites98. Data from animal studies
also suggests that CYP enzymes are responsible for NF metabolism, but no
human data is publicly available identifying specific CYP isoforms, or
associated enzymes, responsible for
biotransformation98,99. NF plasma protein binding is
approximately 50% and not expected to play a significant role in
drug-drug interactions100. This drug is a substrate
for the ABCG2 transporter, commonly known as Breast Cancer Resistance
Protein (BCRP), which has been shown to influence NF transport across
the blood-brain barrier, as well as its excretion into breastmilk30,31,101.
NF apparent volume of distribution is high (V/F = 760 L), suggesting
both an extensive distribution into tissues and also a significant
pre-systemic elimination (i.e., a limited bioavailability), such as that
observed in animal studies 91.
Neither NF optimal dose nor the optimal treatment duration for CD is
well defined. Initially, treatments tended to be long (90–120
days)102 but were subsequently reduced to mimic BZN
treatment spans (approximately 60 days)103,104. The
recent trial CHICO study (NCT02625974) studied alternative dosing (30
versus 60 days) observing similar serological and parasitological
treatment responses for children under 2 years; but in order to apply
these conclusions to all pediatric patients, long term follow-up would
be crucial. Commonly used dose ranges from 8 to 15 mg/kg/day divided in
three daily administrations, but optimal daily dose frequency has never
been duly studied either, and was defined only on the basis of NF
half-life.
The most commonly observed ADRs
are anorexia and weight loss, irritability, sleepiness, and other
nervous system signs and symptoms83,103,105. NF use is
also associated with rash, pruritus, and drug-associated hepatitis but
less frequently than BZN. Depression, peripheral neuropathy, and
psychiatric symptoms have also been reported, less commonly. Similar to
BZN, NF-associated ADRs seem much more common and severe in adults and
are usually mild in children, including
neonates96,106,107. Notably, there is some evidence
that suggests that patients who develop a severe drug reaction to BZN
may still be treated safely with NF 108.
Similar to BZN, NF is considered contraindicated during pregnancy and
lactation: virtually no data is available on the safety of this drug
during the first trimester of pregnancy, and therefore it is still
advisable to avoid its use at this stage. About lactation, recently
published and ongoing studies on NF transfer into breastmilk strongly
suggest that the drug is safe during breastfeeding, and treatment of a
lactating mother should not be discouraged if
needed30,31.