Therapeutic Drug Monitoring of Itraconazole in Endemic Paracoccidioidomycosis: Real-World Data

Therapeutic drug monitoring (TDM) of itraconazole (ITC) has been recommended by international guidelines to optimize efficacy and reduce toxicity, especially in the context of invasive fungal infections. However, whether the same therapeutic targets apply to paracoccidioidomycosis (PCM) remains uncertain.

We conducted a retrospective analysis of patients with proven or probable PCM who used ITC during antifungal treatment between 2016 and 2024 at the University of São Paulo. Two groups were formed: the TDM group and the non-TDM group. Serum samples were obtained at steady-state (≥ 7 days after treatment initiation), and ITC levels were measured by liquid chromatography-mass spectrometry (LC-MS/MS). The institutional standard treatment was ITC capsules at 200 mg once or twice daily, depending on disease severity. Therapeutic serum trough concentrations were defined as 0.5-4.0 mg/L.

Eighty-three patients were included, 18 in the TDM group and 65 in the non-TDM group, predominantly middle-aged males (median age 53 years; 70% male) with the chronic form of PCM (84%). Only 44.4% of initial serum concentrations were within the therapeutic range. Notably, 22% of patients had undetectable serum levels (< 0.014 mg/L). The median ITC concentration was 0.26 mg/L (IQR 0.04-1.95), and no toxic levels were observed. No statistically significant differences were found between the groups regarding ITC dose modification, drug interactions, toxicity, or duration of therapy.

Subtherapeutic serum ITC concentrations were common among PCM patients receiving capsule formulations. Although clinical response was generally favorable, the high variability in absorption highlights the potential value of TDM in selected cases. Prospective studies are warranted to define optimal target levels for PCM management.