Pharmacokinetic Drug Interactions Involving Vortioxetine (Lu AA21004), a Multimodal Antidepressant

BACKGROUND AND OBJECTIVE: The identification and quantification of potential drug–drug interactions is important for avoiding or minimizing the interaction-induced adverse events associated with specific drug combinations. Clinical studies in healthy subjects were performed to evaluate potential pharmacokinetic interactions between vortioxetine (Lu AA21004) and co-administered agents, including fluconazole (cytochrome P450 [CYP] 2C9, CYP2C19 and CYP3A inhibitor), ketoconazole (CYP3A and P-glycoprotein inhibitor), rifampicin (CYP inducer), bupropion (CYP2D6 inhibitor and CYP2B6 substrate), ethinyl estradiol/levonorgestrel (CYP3A substrates) and omeprazole (CYP2C19 substrate and inhibitor). METHODS: The ratio of central values of the test treatment to the reference treatment for relevant parameters (e.g., area under the plasma concentration–time curve [AUC] and maximum plasma concentration [C(max)]) was used to assess pharmacokinetic interactions. RESULTS: Co-administration of vortioxetine had no effect on the AUC or C(max) of ethinyl estradiol/levonorgestrel or 5′-hydroxyomeprazole, or the AUC of bupropion; the 90 % confidence intervals for these ratios of central values were within 80–125 %. Steady-state AUC and C(max) of vortioxetine increased when co-administered with bupropion (128 and 114 %, respectively), fluconazole (46 and 15 %, respectively) and ketoconazole (30 and 26 %, respectively), and decreased by 72 and 51 %, respectively, when vortioxetine was co-administered with rifampicin. Concomitant therapy was generally well tolerated; most adverse events were mild or moderate in intensity. CONCLUSION: Dosage adjustment may be required when vortioxetine is co-administered with bupropion or rifampicin. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40261-013-0117-6) contains supplementary material, which is available to authorized users