Abstract PE10/7
Summary of Pharmacokinetic Drug-drug Interactions for Simeprevir (TMC435), a Hepatitis C Virus NS3/4A Protease Inhibitor Print
S. Ouwerkerk-Mahadevan1, A. Simion2, M. Peeters2, M. Beumont-Mauviel2
1Janssen Research & Development, Beerse, Belgium, 2Janssen Infectious Diseases, Beerse, Belgium
Objective: Simeprevir (SMV [TMC435]) is a potent, oral, once-daily (QD), hepatitis C virus (HCV) NS3/4A protease inhibitor in Phase III trials. Studies investigating the potential for drug interactions between SMV and other medications are reported.
Methods: Multiple clinical studies in healthy volunteers or opioid-dependent subjects receiving methadone investigated the drug interaction potential of SMV when co-administered with commonly prescribed therapies in chronic HCV, such as antiretrovirals, statins, antibiotics, antidepressants, oral contraceptives and immunosuppressants. Effects on exposure (area under the curve; AUC) are presented as least squares mean ratios.
Results: SMV is metabolised via CYP3A; dosing of SMV with the CYP3A inducers efavirenz and rifampin leads to a decrease in SMV plasma concentrations by 71% and 48%, respectively. The CYP3A inhibitors ritonavir and erythromycin lead to a 7-fold increase in SMV plasma concentrations (AUC 7.18- and 7.47-fold higher, respectively). A mild interaction with oral midazolam (45% increase in midazolam), but not with intravenous midazolam, was observed, demonstrating that SMV is a mild inhibitor of intestinal CYP3A but not hepatic CYP3A. SMV inhibits Pgp, which results clinically in a mild elevation in digoxin (39%) plasma concentration when co‑administered. Inhibition of OATP by SMV leads to mild to moderate interactions with statins when co-administered (2.8-fold increase with rosuvastatin, 1.5-fold with simvastatin, 2.1‑fold with atorvastatin).
No clinically relevant changes in PK parameters were observed upon co-administration of SMV with rilpivirine, tenofovir, raltegravir, escitalopram, warfarin, caffeine, omeprazole, dextromethorphan, ethinylestradiol, norethindrone, tacrolimus, cyclosporine or methadone.
Conclusion: SMV can be combined with many agents without dose adjustments, including oral contraceptives, antidepressants, PPIs, warfarin and immunosuppressants. Consequently, HCV regimens containing SMV may have broad potential use across patient populations. Co-administration with strong inhibitors or inducers of CYP3A is not recommended, which may limit use particularly among patients co-infected with HIV/HCV administered ritonavir-boosted protease inhibitors or efavirenz.

Assigned speakers:
Sivi Ouwerkerk-Mahadevan , Janssen Research & Development , Beerse , Belgium

Assigned in sessions:
17.10.2013, 12:00-14:00, Poster Session, Poster Session 1, Exhibition
18.10.2013, 12:00-14:00, Poster Session, Poster Session 2, Exhibition