Background: Rolapitant, a long-acting neurokinin (NK)1 receptor antagonist (RA), has demonstrated efficacy in prevention ofchemotherapy-induced nausea and vomiting in patients administered moderately or highly emetogenic chemotherapy. Unlikeother NK1 RAs, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4, but it does inhibit CYP2D6 and breast cancerresistance protein (BCRP). To analyze potential drug-drug interactions between rolapitant and concomitant medications, thisintegrated safety analysis of four double-blind, randomized phase II or III studies of rolapitant examined adverse events (AEs) byuse versus non-use of drug substrates of CYP2D6 or BCRP. Patients and methods: Patients were randomized to receive either 180mg oral rolapitant or placebo ±1-2 h before chemotherapyin combination with a 5-hydroxytryptamine type 3 RA and dexamethasone. Data for treatment-emergent AEs (TEAEs)and treatment-emergent serious AEs (TESAEs) during cycle 1 were pooled across the four studies and summarized in the overallpopulation and by concomitant use/non-use of CYP2D6 or BCRP substrate drugs. Results: In the integrated safety population, 828 of 1294 patients (64%) in the rolapitant group and 840 of 1301 patients (65%)in the control group experienced at least one TEAE. Frequencies of common TEAEs were similar in the rolapitant and controlpopulations. Overall, 53% of patients received CYP2D6 substrate drugs, none of which had a narrow therapeutic index (likethioridazine or pimozide), and 63% received BCRP substrate drugs. When grouped by concomitant use versus non-use ofCYP2D6 or BCRP substrate drugs, TEAEs and TESAEs occurred with similar frequency in the rolapitant and control populations. Conclusions: The results of this study support the safety of rolapitant as part of an antiemetic triple-drug regimen in patientsreceiving emetogenic chemotherapy, including those administered concomitant medications that are substrates of CYP2D6 orBCRP, such as ondansetron, docetaxel, or irinotecan.