Drug Interactions between conivaptan and simeprevir

GENERALLY AVOID: Coadministration with potent and some moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of simeprevir, which is primarily metabolized by the isoenzyme. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions including rash and photosensitivity. In 24 healthy study subjects administered simeprevir (150 mg once daily) in combination with the moderate CYP450 3A4 and P-glycoprotein substrate/inhibitor erythromycin (500 mg three times a day) for 7 days, mean simeprevir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) increased by approximately 4.5-, 7.5 and 12.7-fold, respectively. Erythromycin Cmax, AUC and Cmin also increased by about 1.6-, 1.9- and 3.1-fold, respectively, presumably due to inhibition of CYP450 3A4 and P-glycoprotein by simeprevir. In another study, simeprevir (200 mg once daily for 7 days) given with the potent CYP450 3A4 inhibitor ritonavir (100 mg twice daily for 15 days) to 12 healthy subjects resulted in approximately 4.7-, 7.2 and 14.4-fold increases in simeprevir Cmax, AUC and Cmin, respectively. Likewise, when simeprevir (50 mg and 150 mg once daily) was given with darunavir/ritonavir (800 mg/100 mg once daily) to 25 healthy subjects for 7 days, simeprevir Cmax, AUC and Cmin increased by about 1.8-, 2.6 and 4.6-fold, respectively, while ritonavir Cmax, AUC and Cmin increased by 1.2-, 1.3 and 1.4-fold, respectively. Darunavir Cmin increased by 1.3-fold.

MANAGEMENT: The use of simeprevir in combination with potent and some moderate CYP450 3A4 inhibitors such as azole antifungal agents, conivaptan, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics should generally be avoided. Some authorities recommend avoiding concomitant use of simeprevir during and for 2 weeks after treatment with itraconazole.