Biopharmaceutical Characteristics of Nifurtimox Tablets for Age‐ and Body Weight‐Adjusted Dosing in Patients With Chagas Disease

Abstract

Treatment of Chagas disease with nifurtimox requires age-and body weight-adjusted dosing, resulting in complex dosing instructions. Appropriate formulations are needed for precise and compliant dosing, especially in pediatric patients. We characterized the biopharmaceutical features of a standard nifurtimox 120-mg tablet and a 30-mg tablet developed to improve dose accuracy. Two open-label, randomized crossover studies were conducted in adult outpatients with Chagas disease.One study investigated whether 4 × 30-mg tablets and 1 × 120-mg tablet were bioequivalent and whether tablets can be administered as an aqueous slurry without affecting bioavailability. The second study investigated the effect of a high-calorie/high-fat diet versus fasting on the absorption of nifurtimox after a single 4 × 30-mg dose. Interventions were equivalent if the 90% confidence interval (CI) of their least-squares (LS) mean ratios for both AUC 0-tlast and C max were in the range of 80%-125%. The 4 × 30-mg and 1 × 120-mg tablet doses were bioequivalent (AUC 0-tlast : LS mean ratio, 104.7%; 90%CI, 99.1%-110.7%; C max : LS mean ratio, 101.7%; 90%CI, 89.4%-115.6%; n = 24). Exposure when giving the 4 × 30-mg dose as a slurry or as tablets was comparable, with an AUC 0-tlast ratio of 93.2% (84.2%-103.1%; n = 12) and a slightly decreased C max ratio for the slurry of 76.5% (68.8%-85.1%). Food improved the bioavailability of nifurtimox substantially (AUC 0-tlast ratio fed/fasted , 172%; 90%CI, 154%-192%; C max ratio fed/fasted , 168%; 90%CI, 150%-187%). The data indicate that the 30-and 120-mg tablets are suitable for dosing adult and pediatric patients accurately; nifurtimox should be administered under fed conditions.

Evaluation of the Anti-Histoplasma capsulatum Activity of Indole and Nitrofuran Derivatives and Their Pharmacological Safety in Three-Dimensional Cell Cultures

“…Additionally, only mild adverse effects were observed in humans [ 17 , 18 ]. Therefore, regulatory agencies such as the Food and Drug Administration (FDA) have approved the commercial use of Nifurtimox in the treatment of Chagas disease [ 18 , 85 ]. Research groups around the world have been carrying out reformulations that make nitrofurans safe for human health and effective against diseases [ 19 , 20 , 25 ].…”

New chemotherapy regimens and biomarkers for Chagas disease: the rationale and design of the TESEO study, an open-label, randomised, prospective, phase-2 clinical trial in the Plurinational State of Bolivia

“…32 33 Moreover, no published popPK for NFX is available and we will use a previously described methodology for BZN 28 101 to validate the popPK for NFX. 113 The new data will provide useful information on the requirements of follow-up duration to assess the true efficacy of chemotherapy in CCD patients. Such efficacy will be evaluated using standard methodologies for CS and qPCR, as well as NCS, such as lytic anti-α-Gal antibodies, 43-48 60 76 antibodies against KMP11, HSP70, PFR2 and peptide 3973, [51][52][53][54][55] and parasite-derived BMK TESA, using an aptamer-based assay, [56][57][58] as described above.…”

Review of pharmacological options for the treatment of Chagas disease

“…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 metabolites 97 , 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 metabolites 98 . 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 biotransformation 98,99 .…”

“…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 neonates 96,106,107 . 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-associated ADRs seem much more common and severe in adults and are usually mild in children, including neonates. 106,116,117 Notably, there is some evidence that suggests that patients who develop a severe drug reaction to BZN may still be treated safely with NF. 118 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.…”