The Effect of Drug-Drug Interactions on the Pharmacokinetics of Isavuconazole: A Comprehensive Review

Isavuconazole is an azole antifungal drug, which is used for invasive aspergillosis and mucormycosis. The objective of this study was to comprehensive review the impact of drug-drug interactions (DDIs) on isavuconazole pharmacokinetics by categorizing concomitant medications as enzyme inducers (eg, rifampicin), inhibitors (eg, ritonavir), or neutral agents. Additionally, we aimed to evaluate whether the duration of combination therapy modulates the magnitude of DDIs and provide references for clinical medication.

The literature concerning the interactions of isavuconazole was systematically retrieved from three retrieval platforms, PUBMED, EMBASE, and the Cochrane Library, using the search terms: "isavuconazole" or "isavuconazonium" or "Cresemba" and "interact*", or "cotreatment", or "coadministration", or "combination", or "concomitant". A total of 1051 articles were retrieved and then conduct screening according to the inclusion and exclusion criteria.

Eleven studies involving 23 drugs were included in this study. Rifampicin, flucloxacillin, and phenobarbital decreased the exposure of isavuconazole. Ketoconazole and ritonavir significantly increased the exposure of isavuconazole. Esomeprazole, had no significant effects on the exposure of isavuconazole. Although midazolam, estradiol/norethisterone, atorvastatin, digoxin, metformin, methotrexate, bupropion, repaglinide, dextromethorphan, caffeine, methadone, warfarin, cyclosporine, tacrolimus, sirolimus, prednisone, and mycophenolate mofetil had also no significant effect on isavuconazole pharmacokinetics, a single-dose administration cannot induce or inhibit metabolic enzymes stably, and we consider the results to be unreliable. Therefore, these drugs still need to be used with caution.

This review demonstrates that drug interactions of isavuconazole are predominantly mediated by the CYP3A4/P-glycoprotein pathway: strong inducers (eg, rifampicin) reduce its exposure, while strong inhibitors (eg, ketoconazole) increase exposure. Single-dose interaction studies are unreliable due to insufficient time for enzyme regulation, highlighting the need to consider the duration of combination therapy. Clinical recommendations: avoid coadministration with strong inducers/inhibitors and implement therapeutic drug monitoring (TDM) for patients on long-term combination therapy to optimize dosing regimens.