The Potential Role of Simeprevir for the Treatment of Hepatitis C

Cristina del Barrio Gascón; Maria Buti


Future Virology. 2015;10(2):67-75. 

In This Article


The chemical name of simeprevir (SMV; TMC435) is (2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropylsulfonyl)-2-[[2-(4-isopropyl-1,3-thiazol-2-yl)-7-methoxy-8-methyl-4-quinolinyl]oxy]-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14 atetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide.

SMV is an inhibitor of the HCV NS3/4A protease, which is essential for viral replication. SMV has antiviral activity in patients infected with HCV genotypes 1, 2, 4, 5 or 6, but has no activity in genotype 3 infection.[13] In an experimental study, SMV inhibited the proteolytic activity of recombinant genotype 1a and 1b HCV NS3/4A proteases, with median Kinetic inhibition constant values of 0.5 and 1.4 nM, respectively.

Properties & Pharmacokinetics

SMV has an oral bioavailability of 65% after a single 150-mg dose. The maximum plasma concentration (Cmax) is attained approximately 4–6 h after administration, and the mean terminal elimination half-life (t1/2, term) is approximately 10 to 13 h in healthy individuals. In HCV-infected patients, the mean t1/2, term was 41.3 h after multiple dosing at 200 mg once daily (q.d.) and steady-state conditions were reached after 7 days of dosing. SMV exposure was generally higher (twofold to threefold) in HCV-infected patients than in healthy persons.

As compared with fasting conditions, the exposure (AUC) of SMV administered as the Phase III 150-mg capsule was 1.69-fold and 1.61-fold higher following a normal breakfast and a high-fat, high-calorie breakfast, respectively. The median time to Cmax was delayed by 1–1.5 h under fed conditions. SMV is predominantly eliminated in the feces. Renal excretion is negligible.[14] Pharmacokinetic studies have been performed in non-HCV-infected patients with moderate or severe hepatic impairment. Compared to healthy individuals with normal hepatic function, the mean steady-state AUC of SMV was 2.4-fold higher in patients with moderate hepatic impairment (Child-Pugh Class B) and 5.2-fold higher in those with severe hepatic impairment (Child-Pugh Class C). In a population pharmacokinetic analysis of HCV-infected patients treated with SMV 150 mg q.d., liver fibrosis stage did not have a clinically relevant effect on SMV pharmacokinetics.

SMV Posology

The recommended SMV dose is one 150-mg capsule once daily for 12 weeks, taken with food.

SMV should not be administered as monotherapy. When considering SMV combination treatment with PEG-IFN/RBV in HCV genotype 1a patients, testing for the NS3 Q80K viral polymorphism should be performed before starting therapy.[15]

Potential Drug Interactions

SMV is mainly metabolized by CYP3A enzymes. Coadministration of SMV with CYP3A-inducing drugs may decrease SMV plasma concentrations and lower the therapeutic effect. Conversely, coadministration of SMV with drugs that inhibit CYP3A enzymes may increase SMV plasma concentrations and increase or prolong the therapeutic and adverse effects.

The impact of SMV on drug-metabolizing enzymes is limited to mild inhibition of CYP1A2 and intestinal (not hepatic) CYP3A. In addition, a potential interaction with P-gp and OATP1ref-1 substrate has been identified.