Impact of Drug-Drug Interactions on Isavuconazole Pharmacokinetics

In recent years, the clinical utility of isavuconazole, an azole antifungal agent, has gained attention due to its effectiveness against invasive fungal infections, particularly invasive aspergillosis and mucormycosis. However, the pharmacokinetics of isavuconazole are significantly influenced by drug-drug interactions (DDIs), raising concerns over its safe and effective use in patients receiving concomitant therapies.

According to a comprehensive review by Yanlei Sang et al. published in the Clinical Pharmacology: Advances and Applications journal on June 17, 2025, DDIs involving isavuconazole primarily occur through the cytochrome P450 3A4 (CYP3A4) and P-glycoprotein pathways. The review systematically assessed 11 studies involving 23 different drugs and categorized the interactions based on the nature of the concomitant medication, identifying strong inducers, inhibitors, and neutral agents.

The study found that potent enzyme inducers such as rifampicin, flucloxacillin, and phenobarbital significantly reduce isavuconazole exposure, while strong inhibitors like ketoconazole and ritonavir can increase it. Specifically, rifampicin was shown to decrease isavuconazole exposure by as much as 97% in phase I studies, necessitating caution in coadministration. In contrast, ketoconazole could increase the AUC (area under the curve) of isavuconazole by over five-fold, indicating a high sensitivity of isavuconazole to CYP3A4 inhibitors.

Furthermore, the duration of combination therapy appears to critically modulate the extent of these interactions. The authors emphasized that single-dose studies may not adequately represent clinical realities, as they fail to account for the time-dependent enzyme regulation that can occur with prolonged drug exposure. This finding underlines the importance of therapeutic drug monitoring (TDM) for patients on long-term isavuconazole therapy to ensure appropriate dosing and mitigate risks associated with DDIs.

The implications of these findings extend beyond pharmacokinetics, highlighting a need for healthcare providers to be vigilant regarding potential DDIs in patients on isavuconazole. The authors advocate for integrating pharmacogenetic data and comprehensive medication reviews to optimize treatment regimens, especially in vulnerable populations such as transplant recipients, who often require complex medication management.

In conclusion, while isavuconazole remains a critical tool in the antifungal arsenal, understanding the nuances of its pharmacokinetics, particularly in relation to DDIs, is essential for maximizing therapeutic outcomes and minimizing adverse effects. Ongoing research and clinical vigilance are necessary as the landscape of antifungal therapy continues to evolve, ensuring that patients receive the safest and most effective care possible.