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.