Co-Administration with Voriconazole Doubles the Exposure of Ruxolitinib in Patients with Hematological Malignancies

Background: Ruxolitinib is newly approved for glucocorticoid-refractory acute graft-versus-host disease (GVHD) in patients undergoing allo-geneic hematopoietic stem-cell transplantation (allo-HSCT), and voriconazole is commonly used in allo-HSCT recipients for the prophylaxis or treatment of invasive fungal infections (IFIs). Drug-drug interaction (DDI) may occur between them because their metabolic pathways overlap and can be inhibited by voriconazole, including cytochrome P450 (CYP) isozymes 3A4 and 2C9.

Objective: In the present study, we aimed to investigate the DDI between ruxolitinib and voriconazole in patients with hematological malignancies.

Methods: A total of 12 patients with hematologic malignancies were enrolled in this single-arm, single-center, Phase I/II, fixed sequence self-control study. All subjects received 5 mg ruxolitinib alone, followed by the co-administration of ruxolitinib and voriconazole. The plasma concentrations of the two drugs were determined by two well-validated high-performance liquid chromatography-tandem mass spectrometry methods. Phoenix WinNonlin software was used to compare the differences in maximum plasma concentration (C_max), time to C_max (T_max), terminal elimination half-life (T_1/2), and apparent plasma clearance (CL/F), as well as area under the curve from time zero to last (AUC_last) and AUC from time zero to infinity (AUC_inf) between the two periods.

Results: After pre-treatment with voriconazole, no significant change existed in T_max, while C_max, T_1/2, AUC_last, and AUC_inf of ruxolitinib were significantly increased by 50.4%, 81.3%, 110.1%, and 118.3%, respectively, and CL/F was significantly decreased to 43.6% compared with patients receiving ruxolitinib alone.

Conclusion: Our findings confirmed a moderate inhibitory DDI between ruxolitinib and voriconazole as voriconazole decreased the elimination and increased the exposure of ruxolitinib in patients with hematologic malignancies. We recommended a dose reduction regimen when voriconazole and ruxolitinib were coadministered. Drug monitoring might help determine the ruxolitinib treatment concentration for aGVHD patients, improve efficacy, and reduce toxicity.