Source: FDA, National Drug Code (US) Revision Year: 2020
Nifurtimox is an antiprotozoal drug [see Microbiology (12.4)].
Nifurtimox exposure-response relationships and the time course of pharmacodynamics response are unknown.
At the recommended dose, nifurtimox treatment does not result in large mean increases (>20 ms) in the QTc interval.
The mean (CV) nifurtimox 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 nifurtimox with food in adult Chagas patients. No clinically significant differences in nifurtimox AUC or Cmax at the 120 mg dose were observed when using two tablet strengths (30 and 120 mg) or administered as whole or dissolved tablets under fed conditions. The median time to reach maximum concentration (Tmax) of nifurtimox under fed conditions was 4 hours (range: 2 to 8 hours).
Following administration of a single oral dose of 120 mg LAMPIT in adult Chagas patients, nifurtimox Cmax increased 68%, AUC increased 71%, and Tmax increased by 1 hour with a high-fat meal (800–1000 calorie, approximately 60% fat) compared to fasted conditions.
Nifurtimox passes the blood brain barrier as well as the placental barrier. The plasma proteins binding of nifurtimox is 42%.
The mean (CV) estimates for elimination half-life of nifurtimox ranged between 2.4–3.6 hours (12–37).
Metabolism of nifurtimox is primarily mediated via nitroreductases. Exploratory investigations identified two major pharmacologically inactive metabolites (M-4, M-6) and several other minor metabolites in pooled human plasma. M-4 is a rearranged cysteine conjugate of nifurtimox with a half-life of approximately 28 hours, and M-6 is postulated to be formed by hydrolytic cleavage of the hydrazone moiety with a half-life of approximately 10 hours.
Following administration of nifurtimox under fed and fasted conditions, approximately 44% and 27% of the dose was recovered in urine mainly as metabolites, respectively. Biliary and fecal elimination of nifurtimox and its metabolites has not been evaluated.
The effect of renal or hepatic impairment on the pharmacokinetics of nifurtimox is unknown. Blood concentrations of nifurtimox increased in patients with ESRD.
No clinical studies evaluating the drug interaction potential of nifurtimox have been conducted.
Cytochrome P450 Enzymes (CYPs): Nifurtimox is not a substrate of CYPs. Nifurtimox and its metabolites (M-4 or M-6) are not inhibitors or inducers of CYPs.
Transporter Systems: Nifurtimox is not a substrate or inhibitor of P-glycoprotein (P-gp) or breast cancer resistant protein (BCRP), and is not an inhibitor of organic anion transporting polypeptide (OATPs), multidrug and toxin extrusion (MATE) proteins (MATE1/MATE2-K), organic anion transporter ⅓ (OAT1/OAT3), or organic cation transporter 2 (OCT2). Major metabolites (M-4 or M-6) of nifurtimox are not inhibitors of P-gp, BCRP, OATPs, MATE1, MATE2K, OAT1, OAT3, or OCT2 at clinically relevant concentrations.
The mechanism of action of nifurtimox is not fully understood. Studies suggest that nifurtimox is metabolized/activated, by Type I (oxygen insensitive) and Type II (oxygen sensitive) nitoreductases (NTR) leading to production of toxic intermediate metabolites and/or reactive oxygen species that induce DNA damage and cell death of both intracellular and extracellular forms of T. cruzi.
Nifurtimox is active against all three stages, trypomastigotes, amastigotes, and epimastigotes, of T. cruzi. However, the sensitivity of T. cruzi strains to nifurtimox, from different geographic regions, may vary.
In vitro studies suggest the potential for development of resistance in T. cruzi against nifurtimox.
The mechanism of resistance to nifurtimox appears to be multifactorial. Trypanosomal nitroreductase is defined as a key resistance determinate. Either loss of gene copy, mutation of gene or down-regulation of gene expression are sufficient to cause decreased susceptibility of T. cruzi against nitroheterocyclic drugs like nifurtimox. In addition, other mechanisms of resistance like lower drug influx or higher drug efflux are described. However, the clinical relevance of these findings is not known.
Nonclinical studies suggest cross-resistance between nifurtimox and benznidazole. This appears to be due to down regulation of Type I NTR localized in the mitochondria.
Adequate long-term carcinogenicity studies for nifurtimox have not been performed. Nitrofurans, which have similar chemical structures to nifurtimox have been reported to be carcinogenic in mice and rats.
The genotoxicity of nifurtimox has been demonstrated in vitro in several bacterial species and mammalian cell systems and in vivo in mammals.
Nifurtimox was mutagenic in strains of S. typhimurium (TA 98, 100, and 1537) in an Ames assay.
Nifurtimox was genotoxic in human lymphocytes in an in vitro micronucleus assay.
In vivo, nifurtimox was shown to be positive for genotoxicity in a mouse micronucleus assay, a mouse sister-chromatid exchange assay, and a human chromosome aberration assay. However, in a sister-chromatid exchange study in humans, oral doses of nifurtimox did not cause a significant increase in the frequency of sister-chromatid exchange in blood lymphocytes.
In a study examining the effects of nifurtimox on testicular morphology, male mice fed 0.08% or 0.16% nifurtimox in animal feed for 14 weeks experienced dose-dependent testicular toxicity including complete inhibition of spermatogenesis with the highest dose, evidence of arrested mitosis, signs of pyknosis, and no mature sperm. However, interstitial cells were unchanged, and fibrosis and inflammatory infiltrates were not observed. Nine weeks after the end of nifurtimox exposure, all testicular effects were almost entirely reversed.
In a male and female fertility study in rats, nifurtimox was administered in dietary feed at doses of 150 ppm (equivalent to 7–15 mg/kg), 300 ppm (equivalent to 15–30 mg/kg/day), and 600 ppm (equivalent to 30–60 mg/kg/day) for 10 weeks before mating. Male fertility was completely inhibited in rats administered 30–60 mg/kg/day nifurtimox, but female fertility was not affected for the same dosing regimen. In a recovery study, 11 weeks after the end of dosing, fertility was still inhibited in 75% of male rats administered nifurtimox for 32 weeks indicating a lack of complete reversibility. The nifurtimox dose in male rats that was not associated with inhibition of fertility was considered to be ≤30 mg/kg/day which is approximately equivalent to 0.5 times the MRHD for fertile males based on body surface area comparison.
The safety and efficacy of LAMPIT for the treatment of Chagas disease in pediatric patients birth to <18 years of age and weighing at least 2.5 kg were demonstrated in one prospective, randomized, double-blind trial conducted in Argentina, Bolivia and Colombia (Trial 1, NCT02625974). Pediatric patients (n=330) with serologic evidence of T. cruzi infection and without Chagas disease-related cardiac or gastrointestinal symptoms were randomly assigned in a 2:1 fashion to a 60-day (n=219) or a 30-day (n=111) nifurtimox treatment regimen. Patients were followed up for one year. LAMPIT was administered three times a day with food using the following body weight-based dosing regimens: pediatric patients weighing <40 kg received a total daily dose of 10-20 mg/kg, and those weighing 40 kg received a total daily dose of 8-10 mg/kg [see Dosage and Administration (2.2)]. Chagas disease diagnosis was confirmed by direct observation of T. cruzi by concentration test in patients <8 months of age at randomization and by demonstrating positive results for both the lysate enzyme-linked immunosorbent assay (ELISA) and the recombinant ELISA in patients ≥8 months to <18 years of age at randomization.
Serological response to treatment was defined as ≥20% decrease in optical density measured by lysate and recombinant ELISA in subjects >8 months to <18 years or seroconversion to negative (defined as negative immunoglobulin G concentration in all patients) at 1-year post-treatment follow-up.
The results for both the lysate ELISA and the recombinant ELISA (Table 5) showed superiority in favor of the nifurtimox 60-day arm compared to the nifurtimox 30-day arm (not an approved dosing regimen).
Table 5. Efficacy results using Lysate ELISA and Recombinant ELISA:
| Lysate ELISA | Recombinant ELISA | |||
|---|---|---|---|---|
| 60-Day N=219 | 30-Day* N=111 | 60-Day N=219 | 30-Day* N=111 | |
| Serological Response | 70 (32%) | 21 (19%) | 76 (35%) | 24 (22%) |
| ≥20% decrease in optical density | 59 (27%) | 15 (14%) | 65 (30%) | 17 (15%) |
| Seroconversion | 11 (5%) | 6 (5%) | 11 (5%) | 7 (6%) |
| Difference (60 day – 30 day), 95% CI, p-value | 13% (3.5%, 22.6%), 0.007 | 13% (3.2%, 23.0%), 0.010 | ||
CI=confidence interval*The 30-day duration is not an approved dosing regimen.
The F29 ELISA detects antibodies to recombinant antigens obtained from the flagellar protein F29 of T. cruzi. Of the 214 patients who were seropositive for the assay at baseline, 46 of 142 (32.4%) in the 60-day nifurtimox treatment arm and 20 of 72 (27.8%) in the 30-day nifurtimox treatment arm (not an approved dosing regimen) seroconverted to negative at the 1-year post-treatment follow-up. Twenty of 59 (33.9%, 95% CI: 22.1%, 47.4%) patients between 6 and 12 years of age in the 60-day arm seroconverted to negative at the 1-year post-treatment follow-up. A similar seroconversion rate was observed in patients 6 and 12 years of age in the 30-day treatment arm. These rates were higher than the 2.8% conversion rate from historical data for untreated patients between 6 and 12 years old at 12 months using the F29 ELISA.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
