Redefining the treatment of Chagas disease: a review of recent clinical and pharmacological data for a novel formulation of nifurtimox

Abstract

Nifurtimox has been used for over 50 years to treat patients with Chagas disease, a potentially life-threatening neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. Without effective antitrypanosomal treatment, the infection can persist and progress to a chronic, often debilitating, clinical form. Migration and urbanization, as well as the shifting distribution of the parasite's insect vector, have contributed to the emergence of Chagas disease as a global health threat. Administration of nifurtimox involves adjusting the dose for age and body weight. Particularly for children, this often requires the previously available 120 mg tablet to be divided manually, which could be problematic. To address this challenge, a new formulation tablet of nifurtimox was developed. Available in two dose strengths, 30 mg and 120 mg, the new formulation tablets contain a functional score line to facilitate accurate division. In addition, the formulation now allows rapid and easy dispersion in water to form a slurry for use by patients with difficulty swallowing tablets. These features enable more accurate body-weight-based and age-appropriate dosing and administration, which should prove beneficial for younger patients, including newborns and babies with a body weight ≥2.5 kg. Development of the new formulation nifurtimox tablets was guided by substantially updating pharmacological and clinical knowledge of the drug to meet current standards and regulatory requirements. This was achieved by conducting a substantial array of additional non-clinical and clinical studies to better understand and characterize clinically relevant aspects of nifurtimox pharmacokinetics. The efficacy and safety of the new tablet in children with Chagas disease was subsequently demonstrated in a large prospective randomized clinical trial with prolonged follow-up. In the present paper, we review key findings that contributed to the successful clinical development of the new formulation nifurtimox tablet, the availability of which redefines the treatment of young patients with Chagas disease.

Fig 1. Main metabolic pathways and resultant metabolites of nifurtimox [42, 43].

According to previous investigations, M-6 and M-4 were the only metabolites (among those quantified), that showed relevant plasma exposure in humans and exceeded or approached the guideline threshold of 10% of total exposure [42,44,45]. Please see the marketing authorization for further safety and drug–drug interaction testing [42,46]. *Indicates position of ¹⁴C label.

Fig 2. The format of the new formulation nifurtimox tablets (upper images show whole 30 mg tablets) allows each 30 mg tablet to be snapped reproducibly into two equal fragments (lower images) [Images from Bayer AG].

Reprinted from Stass H, Just S, Weimann B, Ince I, Willmann S, Feleder E, et al. Eur J Pharm Sci. 2021;166:105940. https://doi.org/10.1016/j.ejps.2021.105940. Copyright 2021, reproduced with permission of Heino Stass [38].

Fig 3. Estimated pediatric exposure to nifurtimox based on body weight adjustment using single-dose ranges (10–20 mg/kg/day and 8–10 mg/kg/day).

Dotted redlines show the 5th (1688 μg.h/L) and 95th (3573 μg.h/L) percentiles. Solid red lines show the median (2441 μg.h/L) of plasma nifurtimox exposure in adults scaled based on a 500 mg daily dose. AUC, area under the curve. Reprinted from Stass H, Ince I, Grossmann U, Weimann B, Willmann S. AAPS J. 2022;24(5):92. https://doi.org/10.1208/s12248-022-00742-w. Copyright2022, under license CC-BY 4.0 and with permission of Springer Nature [54].

Fig 4. Serological response rates (95% CI) to 60-day and 30-day nifurtimox treatment assessed by conventional serological testing 12 months after the end of treatment [40].

Response was defined as seroreduction (in patients aged ≥8 months to <18 years at randomization) or seronegative conversion (in all patients). Seroreduction was defined as at least a 20% reduction in mean optical density measured by two conventional ELISA tests, and seronegative conversion was defined as a negative anti-T. cruzi IgG concentration by two conventional ELISA tests. For placebo, the clinical response rate (95% CI) was derived from a published study [56]. CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; IgG, immunoglobulin G; NFX, nifurtimox.

Fig 5. Kaplan–Meier curves of (A) seronegative conversion(B) ≥20% to 100% seroreduction in patients receiving 60-day or 30-day nifurtimox treatment regimens (full analysis set, N=295).

Patients who received other antitrypanosomal treatments were considered censored. Serological responses were measured by recombinant enzyme-linked immunosorbent assay and indirect hemagglutination assay, and negative results for both tests were required for the patient to be considered to have achieved seronegative conversion. Reprinted from Altcheh J, Sierra V, Ramirez T, Pinto Rocha JJ, Grossmann U, Huang E, et al. Antimicrob Agents Chemother. 2023;67(4):e0119322. https://doi.org/10.1128/aac.01193-22. Copyright 2023, under license CC-BY 4.0 and with permission of the American Society for Microbiology [57].