Comparative Analysis of Isavuconazole DDIs With Other Azole Antifungal Drugs and PBPK Model-Informed Dosing...

Isavuconazole is a broad-spectrum triazole approved for the treatment of invasive aspergillosis or mucormycosis in adults and children aged ≥ 1 year. Current prescribing information lacks guidance regarding the co-administration of isavuconazole with anticancer drugs-limited by the availability of clinical drug-drug interaction (DDI) data in the patient population. This study utilized physiologically-based pharmacokinetic (PBPK) modeling to evaluate the DDI risk of isavuconazole compared with other azoles and provide dosing recommendations when co-administered with anticancer drugs (ibrutinib, venetoclax, and midostaurin). PBPK models were developed in the Simcyp simulator using physiochemical properties, in vitro, and clinical pharmacokinetic data. The model well-predicted isavuconazole pharmacokinetic changes with cytochrome-P450 3A (CYP3A) modulators (itraconazole and rifampicin), and recovered midazolam DDI with isavuconazole as a CYP3A inhibitor. PBPK models for ibrutinib, venetoclax, and midostaurin were developed and validated by comparing simulated and observed pharmacokinetic parameters with and without the CYP3A inhibitor, ketoconazole. The PBPK model predicted area under the plasma concentration-time curve ratios of 2.1, 1.1, and 2.1 for ibrutinib, venetoclax, and midostaurin, respectively, when co-administered with isavuconazole at clinically relevant doses. The findings suggest that isavuconazole can be safely co-administered following appropriate dose adjustments with ibrutinib (50% of normal dose), venetoclax (50-100% of normal dose), or midostaurin (50% of normal dose). Other azoles, posaconazole and voriconazole, showed larger CYP3A-mediated DDIs and consequently require 3-6-fold lower doses of the substrate drugs. In conclusion, this model-informed PK-based dose optimization can enable treatment management in these untested scenarios.