Simeprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated in patient's with HCV genotype 1 for the treatment of chronic hepatitis C virus (HCV) infection. HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients ^[7]. Like all NS3/4A inhibitors, simeprevir is a serine protease inhibitor in similarity to Boceprevir and Telaprevir but is classified as a second generation protease inhibitor. This class of antiviral drugs were the first direct acting antivirals approved but are associated with lower cure rates than newer drugs. Broad use of simeprevir occurred when it was used in combination with a newer drug, Sofosbuvir. Inhibiting HCV NS3/4A protease in a potent and highly specific manner, simeprevir is a direct-acting antiviral agent against the hepatitis C virus. Since the viral protease NS3/4A complex is essential for cleaving the HCV encoded polyprotein into individual viral proteins facilitating replication ^[4], the drug blocks the viral replication process. It is shown to display synergistic effects with interferon-α and HCV NS5B inhibitor, and additive effects with ribavirin in HCV replicon cells ^[2]. Unlike first generation serine protease inhibitors, simprevir has a sightly different resistance profile where limited therapeutic efficacy of the drug is observed with NS3 Q80K polymorphic variants and simeprevir-specific amino acid position of 168 also results in higher treatment failure rates ^[3]. The observed prevalence of the N3 Q80K polymorphism was 30% in subjects infected with HCV genotype 1a and 0.5% in subjects infected with HCV genotype 1b ^[3].

According to 2017 American Association for the Study of Liver Diseases (AASLD) and 2015 consensus guidelines from the Canadian Association for the Study of the Liver (CASL), simeprevir can be used as first-line or second-line threapies for treatment-naïve patients as adjunct to sofosbuvir treatment for genotype 1 or PEG-Interferon/ribavirin combination therapy for genotype 1 or 4. The combination therapy of simeprevir and other antiviral agents are initiated in HCV-positive patients with the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of daily therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality ^[6].

Simeprevir was approved by the FDA in November 2014 and is marketed under the brand name Olysio as oral tablets. Administered once daily with food, 150mg simeprevir capsule is used in combination with Sofosbuvir in patients with HCV genotype 1 without cirrhosis for 12 week duration. In patients with HCV genotype 1 with compensated cirrhosis, the treatment is directed for 24 week duration. Sustained virologic response 12 weeks after planned end of treatment (SVR12) was achieved in 170/176 (97%) subjects without cirrhosis treated with 12 weeks simeprevir in combination with sofosbuvir (FDA Label). The overall SVR12 was 88% (44/50) in treatment-naïve patients with cirrhosis ^[7].

Simeprevir is also used in treatment of HCV genotype 4 patients with or without cirrhosis and is taken with Peginterferon alfa-2a and Ribavirin; this triple therapy allows shortening treatment duration from 48 weeks or longer to 12 or 24 weeks ^[3] depending on prior response status and presence of HIV-1 co-infection. Prior to initiation of treatment with Peginterferon alfa-2a and Ribavirin, screening for the presence of virus with the NS3 Q80K polymorphism is strongly recommended and if detected, alternative treatment should be considered instead to prevent therapeutic failure. The SVR12 was 83% (29/35) in treatment-naïve patients and 86% (19/22) in relapsing patients.

• Amides
• Anti-Infective Agents
• Antiviral Agents
• BCRP/ABCG2 Inhibitors
• BCRP/ABCG2 Substrates
• BSEP/ABCB11 Inhibitors
• Combined Inhibitors of CYP3A4 and P-glycoprotein
• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP1A2 Inhibitors (moderate)
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (moderate)
• Cytochrome P-450 CYP3A4 Substrates
• Enzyme Inhibitors
• Genito Urinary System and Sex Hormones
• Gynecological Antiinfectives and Antiseptics
• NS3/4A Protease Inhibitors
• OATP1B1/SLCO1B1 Substrates
• P-glycoprotein/ABCB1 Inhibitors
• P-glycoprotein/ABCB1 Substrates
• Protease Inhibitors
• Sulfonamides
• Sulfones
• Sulfur Compounds

Indicated for the treatment of adults with chronic hepatitis C virus (HCV) infection: typically in combination with sofosbuvir in patients with HCV genotype 1 without cirrhosis or with compensated cirrhosis and in combination with peginterferon alfa (Peg-IFN-alfa) and ribavirin (RBV) in patients with HCV genotype 1 or 4 without cirrhosis or with compensated cirrhosis.

Resistance: Reduced susceptibility to simeprevir was most commonly associated with the viral NS3 Q80K polymorphism. Amino acid substitutions at NS3 positions S122, R155 and/or D168 are also shown to reduce susceptibility to simeprevir in genotype 1a/b patients.

• Chronic hepatitis C genotype 4
• Genotype 1 chronic hepatitis C infection

Simeprevir is a direct-acting antiviral agent and inhibitor for HCV NS3/4A protease, which is an important enzyme required for viral replication. Unlike Boceprevir and Telaprevir, simeprevir is a competitive, reversible, macrocyclic, noncovalent inhibitor. The macromolecular cyclic portion of the molecule improves the affnity and selectivity characteristics, which allows rapid association and slow dissociation to the protein target through noncovalent binding ^[3].

The mean absolute bioavailability of simeprevir following a single oral 150 mg dose of simeprevir capsule in fed conditions is 62%. Maximum plasma concentrations (Cmax) are typically achieved between 4 to 6 hours following the oral administration.

The volume of distribution for simeprevir has yet to be determined. In animal studies, simeprevir is extensively distributed to gut and liver (liver:blood ratio of 29:1 in rat) tissues.

Simeprevir is extensively (99.9%) bound to plasma proteins, mainly to albumin and to a lesser extent, alpha 1-acid glycoprotein. Increased plasma concentration due to drug-drug interactions is expected when co-administering moderate or strong inhibitors of CYP3A, while the opposite effect is predicted from co-administration of moderate or strong inducers of CYP3A.

Simeprevir is predominantly eliminated through biliary excretion. In a radioactivity study, 91% of radiolabeled drug was detected in the feces and less than 1% was detected in the urine. From the recovered drug in the feces, the unchanged form of simeprevir accounted for 31% of the total administered dose.

The elimination half-life of simeprevir following 200mg dose administration is about 41 hours in HCV-positive patients and 10 to 13 hours in individuals without HCV infection.

The clearance of simeprevir has yet to be determined.

In a combination therapy with sofosbuvir, most common reported adverse effects is fatigue, headache and nausea. In case of triple therapy with PEG-Interferon Alfa-2A and ribavirin, most common adverse effects included rash (including photosensitivity), pruritus and nausea. Elevations of serum bilirubin may be observed due to inhibition of bilirubin transporters OATP1B1 and MRP2 by simeprevir.

• Hepatitis C Virus

• Simeprevir should be taken with food.

1. Raboisson P, de Kock H, Rosenquist A, Nilsson M, Salvador-Oden L, Lin TI, Roue N, Ivanov V, Wahling H, Wickstrom K, Hamelink E, Edlund M, Vrang L, Vendeville S, Van de Vreken W, McGowan D, Tahri A, Hu L, Boutton C, Lenz O, Delouvroy F, Pille G, Surleraux D, Wigerinck P, Samuelsson B, Simmen K: Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350. Bioorg Med Chem Lett. 2008 Sep 1;18(17):4853-8. doi: 10.1016/j.bmcl.2008.07.088. Epub 2008 Jul 24. [PubMed:18678486 ]
2. Kanda T, Nakamoto S, Wu S, Yokosuka O: New treatments for genotype 1 chronic hepatitis C - focus on simeprevir. Ther Clin Risk Manag. 2014 May 24;10:387-94. doi: 10.2147/TCRM.S50170. eCollection 2014. [PubMed:24920913 ]
3. Izquierdo L, Helle F, Francois C, Castelain S, Duverlie G, Brochot E: Simeprevir for the treatment of hepatitis C virus infection. Pharmgenomics Pers Med. 2014 Aug 14;7:241-9. doi: 10.2147/PGPM.S52715. eCollection 2014. [PubMed:25206310 ]
4. Ahmed A, Felmlee DJ: Mechanisms of Hepatitis C Viral Resistance to Direct Acting Antivirals. Viruses. 2015 Dec 18;7(12):6716-29. doi: 10.3390/v7122968. [PubMed:26694454 ]
5. Cummings MD, Lindberg J, Lin TI, de Kock H, Lenz O, Lilja E, Fellander S, Baraznenok V, Nystrom S, Nilsson M, Vrang L, Edlund M, Rosenquist A, Samuelsson B, Raboisson P, Simmen K: Induced-fit binding of the macrocyclic noncovalent inhibitor TMC435 to its HCV NS3/NS4A protease target. Angew Chem Int Ed Engl. 2010 Feb 22;49(9):1652-5. doi: 10.1002/anie.200906696. [PubMed:20166108 ]
6. Myers RP, Shah H, Burak KW, Cooper C, Feld JJ: An update on the management of chronic hepatitis C: 2015 Consensus guidelines from the Canadian Association for the Study of the Liver. Can J Gastroenterol Hepatol. 2015 Jan-Feb;29(1):19-34. Epub 2015 Jan 13. [PubMed:25585348 ]
7. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance. http://hcvguidelines.org. Accessed June 12, 2017. [Link]

• J05AE — Protease inhibitors
• J05A — DIRECT ACTING ANTIVIRALS
• J05 — ANTIVIRALS FOR SYSTEMIC USE
• J — ANTIINFECTIVES FOR SYSTEMIC USE

• G01AE — Sulfonamides
• G01A — ANTIINFECTIVES AND ANTISEPTICS, EXCL. COMBINATIONS WITH CORTICOSTEROIDS
• G01 — GYNECOLOGICAL ANTIINFECTIVES AND ANTISEPTICS
• G — GENITO URINARY SYSTEM AND SEX HORMONES