Impact of Concomitant Metamizole Treatment on the Exposure of Mould-Active Triazoles

Metamizole is an analgesic drug with moderate cytochrome P450 (CYP) inductive properties. The antifungal triazoles are metabolized by several CYP enzymes, but the interaction with metamizole remains poorly described. We investigated the influence of metamizole on the exposure of voriconazole, isavuconazole, and posaconazole.

Patients from UZ Leuven (Belgium) and Ljubljana University Medical Centre (Slovenia) receiving voriconazole, isavuconazole, or posaconazole concomitantly with metamizole were included in the study. Routine therapeutic drug monitoring (TDM) measurements collected between January 2019 and December 2024 were retrieved retrospectively. TDM concentrations outside of concomitant therapy were collected as controls. The influence of metamizole and other clinically relevant covariates was analysed using generalized estimating equations (GEE).

A total of 126 distinct treatments with a triazole from 115 patients, accounting for 392 measurements, were included in the study. GEE analysis revealed a significant negative association between the 7-day cumulative metamizole dose and lower voriconazole and posaconazole concentrations. Additionally, C-reactive protein had a positive association with voriconazole concentrations. Only ICU admission and patient characteristics, that is, sex and weight, had a significant influence on isavuconazole concentrations.

Concomitant therapy with metamizole led to lower voriconazole and posaconazole concentrations, presumably through induction of CYP enzymes and possibly UDP-glucuronyltransferase. We recommend avoiding concomitant use of metamizole with the antifungal triazoles to prevent underexposure and treatment failure or frequent TDM if the combination cannot be avoided. Further studies are needed to confirm our findings and investigate the influence of metamizole on other triazoles.