In vivo Metabolism of Nifurtimox and the Drug-Drug Interaction Potential Including its Major Metabolites

Title:In vivo Metabolism of Nifurtimox and the Drug-Drug Interaction Potential Including its Major Metabolites

Volume: 24 Issue: 8

Author(s): Simone I. Schulz*, Dieter Lang, Gabriele Schmuck, Michael Gerisch, Michaela Bairlein, Robert Fricke and Heino Stass

Affiliation:

• Bayer AG, 42096 Wuppertal, Germany

Abstract:

Background: Nifurtimox is an effective treatment for patients with Chagas disease, but knowledge of its biotransformation and excretion is limited.

Objective: This study aimed to better understand the fate of oral nifurtimox in vivo.

Methods: We investigated the exposure and excretion pathways of [¹⁴C]-labeled nifurtimox and its metabolites in rats. We then quantified the prominent metabolites and nifurtimox in the urine and plasma of patients receiving nifurtimox using LC-HRMS with reference standards and quantified these compounds in rat plasma after a single, high dose of nifurtimox. We also investigated potential drug-drug interactions (DDIs) of these compounds in vitro.

Results: In rats, orally administered nifurtimox was rapidly absorbed (t_max 0.5 h) and eliminated (t_½ 1.4 h). Metabolism of nifurtimox yielded six predominant metabolites (M-1 to M-6) in urine and plasma, and the dose was excreted equally via the renal and fecal routes with only traces of unchanged nifurtimox detectable due to its instability in excreta. In patients with Chagas disease, only M-6 and M-4 achieved relevant exposure levels, and the total amount of excreted metabolites in urine was higher in fed versus fasted patients, consistent with the higher systemic exposure. For nifurtimox, M-6, and M-4, no potential perpetrator pharmacokinetic DDIs with the main cytochrome P- 450 enzymes and drug transporters were identified in vitro.

Conclusion: This contemporary analysis of the complex metabolite profile and associated exposures emerging after oral dosing of nifurtimox in rats and humans, together with the expected low risk for clinically relevant DDIs, expands the understanding of this important anti-trypanosomal drug.

Cite this article as:

Schulz I. Simone*, Lang Dieter, Schmuck Gabriele, Gerisch Michael, Bairlein Michaela, Fricke Robert and Stass Heino, In vivo Metabolism of Nifurtimox and the Drug-Drug Interaction Potential Including its Major Metabolites, Current Drug Metabolism 2023; 24 (8) . https://dx.doi.org/10.2174/1389200224666230817114758