Evaluation of Adverse Events in Patients with Bortezomib Concomitantly used with Azole-based Antifungal Agents

Abstract

The main metabolic pathway of bortezomib is related to cytochrome P450 (CYP) 3A4. Azole-based antifungal agents are typical CYP3A4 inhibitors and frequently administered for hematological diseases as prophylaxis or treatment. It is important to evaluate the clinical impacts of drug interactions between bortezomib and azole-based antifungal agents, with the view of providing better treatment. In this study, we investigated in 73 patients, who received bortezomib therapy, for the occurrence of adverse events such as hematotoxicity and peripheral neuropathy: combination with an azole-based antifungal group (n = 22) and bortezomib alone group (n = 51). The incidence of Grade 3/4 leukopenia and sensory peripheral neuropathy in the combination group was increased significantly compared to the bortezomib group (45.5％ > 17.6％, 27.3％ > 3.9％, respectively; both P < 0.05). Leukopenia was observed in the combination group gradually after adding an azole antifungal. The decrease ratio was significantly higher in patients with voriconazole or itraconazole, and the days to nadir were shorter in patients with voriconazole or itraconazole (median 11 days; P < 0.01). The number of patients with progression of sensory peripheral neuropathic was similar in both groups; however, the days to exacerbation were shorter in patients with voriconazole or itraconazole (median 14.5 days; P < 0.05). Concomitant use of azole-based antifungal agents might exacerbate bortezomib-induced adverse events (i.e. leukopenia and sensory peripheral neuropathy); therefore, health care professionals should closely monitor adverse events when bortezomib is administered with azole-based antifungal agents.