Impact of Concomitant Use of Azoles on Bortezomib-related Adverse Drug Reactions Using JADER.

Abstract

Azoles are widely used for prophylaxis in patients with haematologic malignancies and are well known as selective cytochrome P450 isoenzyme 3A4 inhibitors. Although the interaction between bortezomib and azoles has been reported, most previous studies were case reports or small clinical studies. Hence, we conducted a pharmacoepidemiological study to elucidate the impact of azoles on bortezomib-related adverse reactions, using the Japanese adverse drug event report database (JADER). We extracted 19,567 reports on patients prescribed bortezomib and/or azoles. We classified cases into three groups, namely bortezomib, bortezomib and azoles, and azoles groups. We estimated the odds ratios (OR) for the impact of concomitant azole use on five bortezomib-related adverse drug reactions (peripheral neuropathy, thrombocytopenia, neutropenia, leukopenia, and interstitial lung disease) using logistic regression. The OR for peripheral neuropathy in the 'bortezomib and azoles' group was higher than that in the bortezomib group [OR=2.02, 95% confidence interval (CI)=1.32-3.08]. The magnitude of the interaction was stronger with itraconazole than that with fluconazole (itraconazole, OR=3.22, 95% CI=1.78-5.70; fluconazole, OR=1.56, 95% CI=0.86-2.72). We found an association between concomitant administration of azoles with bortezomib and peripheral neuropathy. Azoles may enhance bortezomib-induced peripheral neuropathy based on their pharmacokinetic properties.