Fluconazole

This fixed‑sequence, open‑label study in healthy volunteers examined the effect of the dual CYP3A4/CYP2C19 inhibitor fluconazole on the pharmacokinetics of a single 100 mg dose of fedratinib, a JAK2‑selective inhibitor for myelofibrosis. Coadministration with fluconazole raised fedratinib’s peak plasma concentration by 21% and the area under the concentration‑time curve (AUC) by 56% compared with fedratinib alone. Both regimens were well tolerated, with no unexpected safety signals. The findings demonstrate a moderate drug‑drug interaction that may require dose adjustment or monitoring when fedratinib is used together with potent CYP3A4/CYP2C19 inhibitors.

Fig. 1 Mean plasma fedratinib concentration–time profiles following single oral doses of fedratinib alone or in combination with fluconazole. (Chen Y, et al., 2022)

A series of fluconazole analogues bearing alkyl, aryl, cycloalkyl, or dialkyl‑amino substituents were synthesized and tested. Several compounds exhibited broad‑spectrum antifungal activity with excellent MIC values against multiple clinical isolates. Notably, the most promising analogues were less hemolytic than voriconazole, the least hemolytic FDA‑approved azole. Mechanistic studies showed chain‑dependent fungal membrane disruption and inhibition of ergosterol biosynthesis. These novel azole derivatives address the limitations of current azoles (fungistatic action and toxicity) and offer potential for further development.

Fig. 2 3D bar graph depicting the dose-dependent hemolytic activity of azole derivatives 6-10 and VOR against mRBCs. (Thamban Chandrika N, et al., 2018)