Simeprevir

Last updated

Simeprevir
Simeprevir.svg
Clinical data
Pronunciation /sɪˈmɛprəvɪər/
si-MEP-rə-veer
Trade names Olysio, Sovriad, Galexos, others
Other namesTMC435; TMC435350
AHFS/Drugs.com Monograph
MedlinePlus a614013
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) [1]
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 62% (under fed conditions)
Protein binding >99.9%
Metabolism Liver (CYP3A, CYP2C8, CYP2C19)
Elimination half-life 10–13 hours (HCV-uninfected subjects), 41 hours (HCV-infected subjects)
Excretion Feces (91%), urine (<1%)
Identifiers
  • (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,12,13,14,14a-tetradecahydrocyclopenta[c]cyclopropa[g] [1,6]diazacyclotetradecine-12a(1H)-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.215.933 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C38H47N5O7S2
Molar mass 749.94 g·mol−1
3D model (JSmol)
    • Cc1c(ccc2c1nc(cc2O[C@@H]3C[C@@H]4[C@@H](C3)C(=O)N(CCCC/C=C\[C@@H]5C[C@]5(NC4=O)C(=O)NS(=O)(=O)C6CC6)C)c7nc(cs7)C(C)C)OC
    • InChI=1S/C38H47N5O7S2/c1-21(2)30-20-51-35(40-30)29-18-32(26-13-14-31(49-5)22(3)33(26)39-29)50-24-16-27-28(17-24)36(45)43(4)15-9-7-6-8-10-23-19-38(23,41-34(27)44)37(46)42-52(47,48)25-11-12-25/h8,10,13-14,18,20-21,23-25,27-28H,6-7,9,11-12,15-17,19H2,1-5H3,(H,41,44)(H,42,46)/b10-8-/t23-,24-,27-,28-,38-/m1/s1
    • Key:JTZZSQYMACOLNN-VDWJNHBNSA-N

    Simeprevir, sold under the brand name Olysio among others, is a medication used in combination with other medications for the treatment of hepatitis C. [2] It is specifically used for hepatitis C genotype 1 and 4. [2] Medications it is used with include sofosbuvir or ribavirin and peginterferon-alfa. [2] Cure rates are in 80s to 90s percent. [3] [4] [5] It may be used in those who also have HIV/AIDS. [2] It is taken by mouth once daily for typically 12 weeks. [2]

    Contents

    Common side effects include feeling tired, headache, rash, itchiness, and sensitivity to sunlight. [2] In those with previous hepatitis B infection, active disease may recur. [2] It is not recommended in those with significant liver problems. [2] During pregnancy when used with ribavirin it may cause harm to the baby while when used with sofosbuvir its safety is unclear. [2] [6] Simeprevir is a HCV protease inhibitor. [2]

    Simeprevir was developed by Medivir AB and Janssen Pharmaceutica. [7] It was approved for medical use in the United States in 2013. [8] It was removed from the World Health Organization's List of Essential Medicines in 2019. [9] [10] It is not available as a generic medication as of 2015. [6]

    Medical use

    Simeprevir is indicated treating chronic hepatic C (CHC) infection as a part of a triple antiviral treatment regimen consisting of two other drugs: peginterferon-alfa (PEG-IFN) and ribavirin (RBV). [11] It is primarily effective in treating Hepatitis C virus (HCV) genotype 1 infected subjects with compensated liver disease, including cirrhosis. [11] There are currently no studies that show Simeprevir's effectiveness as a single therapy for HCV. [11] Simeprevir is generally used for HCV genotype 1 infected subjects, but off-label medical use has been indicated for type 4 genotype as well. [12]

    Dosing

    Simeprevir is dosed along with peg-IFN and RBV as triple therapy. [11] Appropriate dosing of Simeprevir is dependent upon the patient's liver function, kidney function, viral load, and HCV genotype. [11] This medication is not recommended for people with moderate or severe liver impairment and people with end-stage kidney disease since Simprevir was not studied for use in these patient populations. [11] Simeprevir might be discontinued depending on their viral load. [11] For instance, if the patient's viral load is detectable (>25 units/mL) during the 4th week of their treatment regimen, it is considered an inadequate treatment and simeprevir must be discontinued. [11]

    Contraindications

    Any contraindications that apply to peg-IFN and RBV apply to simeprevir since they must be used in combination during treatment of CHC. For example, people with sickle cell anemia are contraindicated to RBV therapy and are therefore contraindicated to simeprevir and peg-IFN combination therapy. [13] Pregnant women and men whose female partners are pregnant are contraindicated for simeprevir since peg-IFN and RBV are known to cause birth defects. [11] [13] [14]

    Pregnancy

    Simeprevir is avoided in pregnant women or women planning to be pregnant because it going to be taken with RBV and Peg-IFN, which have both shown to cause fetal problems in animal studies. [11] [13] [14] RBV has been shown to cause birth defects and fetal deaths in animal studies. [13] Peg-IFN has been shown to cause abortions in animal studies. [14] People must have a negative pregnancy test prior to starting therapy, use at least two effective birth control methods during treatment, and undergo monthly pregnancy tests. [11] If pregnant women are exposed to any medication regimen containing ribavirin, they are encouraged to report this through the ribavirin pregnancy registry. [13]

    Adverse effects

    Severe itching (22%), sensitivity to sunlight (5%), and rash (25%) are some of the common adverse effects of simeprevir. [15] Other side effects may include nausea, muscle pain, difficulty breathing and increased bilirubin. [16] It may reactivate hepatitis B in those who have been previously infected. [17] The European Medicines Agency (EMA) has recommended screening all people for hepatitis B before starting simeprevir for hepatitis C in order to minimize the risk of hepatitis B reactivation. [18]

    Combination treatment

    In March 2015, Gilead Sciences e-mailed warnings to health care providers about nine people that began taking its hepatitis C drugs ledipasvir/sofosbuvir or sofosbuvir along with amiodarone, daclatasvir, or simeprevir developed abnormally slow heartbeats and one died of cardiac arrest. Three required a pacemaker to be inserted. Gilead said the combinations aren't recommended and product labels will be updated. [19]

    Mechanism of action

    Simeprevir is a hepatitis C virus protease inhibitor. [20]

    Simeprevir is a NS3/4A protease inhibitor, thus preventing viral maturation through inhibition of protein synthesis. Simeprevir is administered as one capsule once daily with pegylated interferon and ribavirin for the treatment of genotype 1 or genotype 4 chronic hepatitis C in adult people with compensated liver disease (including cirrhosis), with or without HIV-1 co-infection, who are treatment naive or who have failed previous interferon therapy. [21] [22] Genotype 1 is the most prevalent form of hepatitis C virus (HCV) worldwide.[ citation needed ]

    Pharmacokinetics

    Simeprevir is orally bioavailable. Its absorption increases when taken with food, and is therefore advised to be taken with food. [11] The liver's CYP3A4 enzymes mainly break down simeprevir, but CYP2C8 and CYP2C19 enzymes can also play a role. [11] Its half-life in the plasma is 41 hours in people with HCV. [11] Its peak effect happens 4 to 6 hours after taking the medication. [11] It is primarily excreted into the feces (91%). [11]

    Pharmacogenomics

    According to simeprevir's prescriber information, its efficacy in combination with peginterferon alfa and ribavirin is "substantially reduced in people with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to people infected with HCV genotype 1a without Q80K polymorphism." [11] People with Q80K polymorphism are not advised to take simeprevir. [11]

    Drug interactions

    Simeprevir is a CYP3A4 substrate so its plasma concentration will significantly increase if taken with medications that are strong CYP3A4 inhibitors (i.e. erythromycin, ritonavir) and will significantly decrease if taken with strong CYP3A4 inducers (i.e. efavirenz, rifampin, Saint John's wort). [11] Simeprevir also inhibits intestinal (but not liver) CYP3A. For instance, midazolam, an anticonvulsant, gets metabolized by intestinal CYP3As and taking it with simeprevir can lead to increased midazolam levels that can be toxic. [11] Simeprevir also inhibits OATP1B1/3 and P-glycoprotein (P-gp) transporters, which are normally transporters that pump out drug out of the plasma. [11] [23] Thus, taking simeprevir with medications that are substrates for these transporters can lead to increased plasma concentrations of these medications. For example, calcium channel blockers (i.e. diltiazem, amlodipine) are P-gp substrates and can lead to increased concentrations of these drugs when taken with simeprevir. [11] Taking ciclosporin, a substrate for OATP1B1/3, with simeprevir resulted in significant increase in ciclosporin concentration and are therefore not recommended to be taken together. [11]

    Approval

    In the United States, it is approved by the Food and Drug Administration (FDA) for use in combination with peginterferon-alfa and ribavirin for hepatitis C. [24] Simeprevir has been approved in Japan for the treatment of chronic hepatitis C infection, genotype 1. [25]

    Clinical study

    Simeprevir has been tested in combination regimens with pegylated interferon alfa-2a and ribavirin, [26] and in interferon-free regimens with other direct-acting antiviral agents including daclatasvir [27] and sofosbuvir. [28]

    Results from three phase 3 randomized, double-blind, placebo controlled clinical trials (C208, C216, and HPC3007) in people with chronic HCV GT1 were favourable and resulted in FDA supporting the approval of simeprevir for Hepatitis C genotype 1. [15] Members of the FDA commented following a presentation by Johnson & Johnson (24 October 2013) that post-marketing studies in racial and ethnic minorities, people co-infected with HIV, and other underrepresented populations are needed.[ citation needed ]

    SARS-CoV-2 research

    Several studies have been testing if the virostatic mechanism of FDA approved direct acting agents, including simeprevir in combination with remdesivir (relevant drug during the Ebola epidemic 2014–2016), could be of use in the fight against the global pandemic of Sars-Cov-2. Paritaprevir, another molecule used to treat Hepatitis type C, also showed promising results in terms of binding energy and stability of the complex formed. [29]

    The advantage of working with such compounds is that they are already FDA approved antivirals, which means that clinical trial phases can be initiated more quickly. The speed of medical response is a critical factor influencing the global consequences of the pandemic; the faster antidotes such as drugs and/ or vaccines are available on a large scale, the more promising is the containment of the disease and its (economic) consequences. Speed is a crucial factor, especially regarding the fight of viruses, which by nature have an extremely high mutation rate.[ citation needed ]

    For SARS-CoV-2, simeprevir acts by inhibiting Main protease (Mpro) and RNA-dependent RNA polymerase, a non-structural protein, essential for viral RNA synthesis. [29]

    Mpro belongs to the same enzyme class as NS3/4A, the serine proteases. It cleaves the translated polyprotein to form proteins elemental to viral transcription and replication. Remdesivir alone only inhibits the polymerase itself; in order to stop viral synthesis, an approved hepatitis C drug is also administered to stop the spread of the virus. [29]

    In vitro, the viral infection of Sars-CoV-2 could be stopped, and in addition it could be observed that further proteases of the virus are inhibited, and the effect of the antiviral could thus be enhanced. In this regard, clinical studies proving the efficiency on the organism are still lacking at present, which are required before using the drug combination on a large scale as a form of therapy against a Sars-CoV-2 infection.[ citation needed ]

    The hepatitis drugs are considered potential inhibitors of SARS-CoV-2 Mpro in the fight against COVID-19 infection, and the binding affinity and its mechanism, as well as the stability of the complexes formed this way, may serve as a guideline or even template when it comes to designing inhibitors that specifically target this virus. The compounds themselves may also play an important role and shall be studied further in clinical trials.[ citation needed ]

    Related Research Articles

    <span class="mw-page-title-main">Hepatitis C</span> Human viral infection

    Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include fever, dark urine, abdominal pain, and yellow tinged skin. The virus persists in the liver, becoming chronic, in about 70% of those initially infected. Early on, chronic infection typically has no symptoms. Over many years however, it often leads to liver disease and occasionally cirrhosis. In some cases, those with cirrhosis will develop serious complications such as liver failure, liver cancer, or dilated blood vessels in the esophagus and stomach.

    <span class="mw-page-title-main">Hepatitis C virus</span> Species of virus

    The hepatitis C virus (HCV) is a small, enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer and lymphomas in humans.

    Pegylated interferon alfa-2a, sold under the brand name Pegasys among others, is medication used to treat hepatitis C and hepatitis B. For hepatitis C it is typically used together with ribavirin and cure rates are between 24 and 92%. For hepatitis B it may be used alone. It is given by injection under the skin.

    Pegylated interferon alfa-2b is a drug used to treat melanoma, as an adjuvant therapy to surgery. Also used to treat hepatitis C, it is no longer recommended due to poor efficacy and adverse side-effects. Subcutaneous injection is the preferred delivery method.

    <span class="mw-page-title-main">Boceprevir</span> Chemical compound

    Boceprevir is a protease inhibitor used to treat hepatitis caused by hepatitis C virus (HCV) genotype 1. It binds to the HCV nonstructural protein 3 active site.

    <span class="mw-page-title-main">Telaprevir</span> Chemical compound

    Telaprevir (VX-950), marketed under the brand names Incivek and Incivo, is a pharmaceutical drug for the treatment of hepatitis C co-developed by Vertex Pharmaceuticals and Johnson & Johnson. It is a member of a class of antiviral drugs known as protease inhibitors. Specifically, telaprevir inhibits the hepatitis C viral enzyme NS3/4A serine protease. Telaprevir is only indicated for use against hepatitis C genotype 1 viral infections and has not been proven to be safe or effective when used for other genotypes of the virus. The standard therapy of pegylated interferon and ribavirin is less effective than telaprevir in those with genotype 1.

    <span class="mw-page-title-main">Sofosbuvir</span> Chemical compound

    Sofosbuvir, sold under the brand name Sovaldi among others, is a medication used to treat hepatitis C. It is taken by mouth.

    <span class="mw-page-title-main">Daclatasvir</span> Chemical compound

    Daclatasvir, sold under the brand name Daklinza, is an antiviral medication used in combination with other medications to treat hepatitis C (HCV). The other medications used in combination include sofosbuvir, ribavirin, and interferon, vary depending on the virus type and whether the person has cirrhosis. It is taken by mouth.

    <span class="mw-page-title-main">Ledipasvir</span> Hepatitis C drug

    Ledipasvir is a drug for the treatment of hepatitis C that was developed by Gilead Sciences. After completing Phase III clinical trials, on February 10, 2014, Gilead filed for U.S. approval of a ledipasvir/sofosbuvir fixed-dose combination tablet for genotype 1 hepatitis C. The ledipasvir/sofosbuvir combination is a direct-acting antiviral agent that interferes with HCV replication and can be used to treat patients with genotypes 1a or 1b without PEG-interferon or ribavirin.

    <span class="mw-page-title-main">Dasabuvir</span> Chemical compound

    Dasabuvir, sold under the brand name Exviera, is an antiviral medication for the treatment of hepatitis C. It is often used together with the combination medication ombitasvir/paritaprevir/ritonavir specifically for hepatitis C virus (HCV) type 1. Ribavirin may also additionally be used. These combinations result in a cure in more than 90% of people. It is taken by mouth.

    <span class="mw-page-title-main">Ledipasvir/sofosbuvir</span> Medication used to treat hepatitis C

    Ledipasvir/sofosbuvir, sold under the trade name Harvoni among others, is a medication used to treat hepatitis C. It is a fixed-dose combination of ledipasvir and sofosbuvir. Cure rates are 94% to 99% in people infected with hepatitis C virus (HCV) genotype 1. Some evidence also supports use in HCV genotype 3 and 4. It is taken daily by mouth for 8–24 weeks.

    Ombitasvir/paritaprevir/ritonavir, sold under the brand name Technivie among others, is a medication used to treat hepatitis C. It is a fixed-dose combination of ombitasvir, paritaprevir, and ritonavir. Specifically it is used together with dasabuvir or ribavirin for cases caused by hepatitis C virus genotype 1 or 4. Cure rates are around 95%. It is taken by mouth.

    <span class="mw-page-title-main">Beclabuvir</span> Chemical compound

    Beclabuvir is an antiviral drug for the treatment of hepatitis C virus (HCV) infection that has been studied in clinical trials. In February 2017, Bristol-Myers Squibb began sponsoring a post-marketing trial of beclabuvir, in combination with asunaprevir and daclatasvir, to study the combination's safety profile with regard to liver function. From February 2014 to November 2016, a phase II clinical trial was conducted on the combination of asunaprevir/daclatasvir/beclabuvir on patients infected with both HIV and HCV. Furthermore, a recent meta-analysis of six published six clinical trials showed high response rates in HCV genotype 1-infected patients treated with daclatasvir, asunaprevir, and beclabuvir irrespective of ribavirin use, prior interferon-based therapy, or restriction on noncirrhotic patients, IL28B genotype, or baseline resistance-associated variants

    <span class="mw-page-title-main">Grazoprevir</span> Drug approved for the treatment of hepatitis C

    Grazoprevir is a drug approved for the treatment of hepatitis C. It was developed by Merck and completed Phase III trials, used in combination with the NS5A replication complex inhibitor elbasvir under the trade name Zepatier, either with or without ribavirin.

    Elbasvir/grazoprevir, sold under the brand name Zepatier, is a fixed-dose combination for the treatment of hepatitis C, containing elbasvir and grazoprevir. It is used to treat chronic hepatitis C virus (HCV) genotypes 1 or 4 infection in both treatment-naïve and treatment-experienced patients.

    <span class="mw-page-title-main">Narlaprevir</span> Chemical compound

    Narlaprevir, is an inhibitor of NS3/4A serine protease, intended for the treatment of chronic hepatitis C caused by genotype 1 virus in combination with other antiviral drugs.

    Sofosbuvir/velpatasvir, sold under the brand name Epclusa among others, is a fixed-dose combination medication for the treatment of hepatitis C in adults. It combines sofosbuvir and velpatasvir. It is more than 90% effective for hepatitis C genotypes one through six. It also works for hepatitis C in those who also have cirrhosis or HIV/AIDS. It is taken by mouth.

    <span class="mw-page-title-main">NS5B inhibitor</span> Class of pharmaceutical drugs

    Non-structural protein 5B (NS5B) inhibitors are a class of direct-acting antivirals widely used in the treatment of chronic hepatitis C. Depending on site of action and chemical composition, NS5B inhibitors may be categorized into three classes—nucleoside active site inhibitors (NIs), non-nucleoside allosteric inhibitors, and pyrophosphate analogues. Subsequently, all three classes are then subclassified. All inhibit RNA synthesis by NS5B but at different stages/sites resulting in inability of viral RNA replication. Expression of direct-acting NS5B inhibitors does not take place in cells that are not infected by hepatitis C virus, which seems to be beneficial for this class of drugs.

    The term Direct-acting antivirals (DAA) has long been associated with the combination of antiviral drugs used to treat hepatitis C infections. These are the more effective than older treatments such as ribavirin and interferon. The DAA drugs against hepatitis C are taken orally, as tablets, for 8 to 12 weeks. The treatment depends on the type or types (genotypes) of hepatitis C virus that are causing the infection. Both during and at the end of treatment, blood tests are used to monitor the effectiveness of the treatment and subsequent cure.

    <span class="mw-page-title-main">Interferon Lambda 4</span> Protein-coding gene in the species Homo sapiens

    Interferon lambda 4 is one of the most recently discovered human genes and the newest addition to the interferon lambda protein family. This gene encodes the IFNL4 protein, which is involved in immune response to viral infection.

    References

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    3. ↑ "Initial treatment of HCV infection". www.hcvguidelines.org. October 2016. Archived from the original on 7 December 2016. Retrieved 1 December 2016.
    4. ↑ Majumdar A, Kitson MT, Roberts SK (June 2016). "Systematic review: current concepts and challenges for the direct-acting antiviral era in hepatitis C cirrhosis". Alimentary Pharmacology & Therapeutics. 43 (12): 1276–92. doi: 10.1111/apt.13633 . PMID   27087015.
    5. ↑ Brochot E, Helle F, François C, Castelain S, Capron D, Nguyen-Khac E, Duverlie G (April 2015). "Which therapeutic option for hepatitis C virus genotype 1?". Scandinavian Journal of Gastroenterology. 50 (4): 470–8. doi:10.3109/00365521.2014.978364. PMID   25396710. S2CID   34382861.
    6. 1 2 Hamilton R (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 80. ISBN   9781284057560.
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    19. ↑ West, Stephen. "Gilead Warns After Hepatitis Patient on Heart Drug Dies" Archived 2017-03-22 at the Wayback Machine . Published 21 March 2015.
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    23. ↑ Furihata T, Matsumoto S, Fu Z, Tsubota A, Sun Y, Matsumoto S, et al. (August 2014). "Different interaction profiles of direct-acting anti-hepatitis C virus agents with human organic anion transporting polypeptides". Antimicrobial Agents and Chemotherapy. 58 (8): 4555–64. doi:10.1128/AAC.02724-14. PMC   4135986 . PMID   24867984.
    24. ↑ "FDA approves new treatment for hepatitis C virus". Food and Drug Administration. 22 November 2013. Archived from the original on 16 December 2013.
    25. ↑ "Medivir: Simeprevir has been approved in Japan for the treatment of genotype 1 chronic hepatitis C infection". The Wall Street Journal. 27 September 2013. Archived from the original on 24 November 2013.
    26. ↑ "Phase 3 Studies Show Simeprevir plus Interferon/Ribavirin Cures Most Patients in 24 Weeks". hivandhepatitis.com. 27 December 2012. Archived from the original on 13 March 2013.
    27. ↑ Medivir announces TMC435 in an expanded clinical collaboration. Medivir. 18 April 2012.
    28. ↑ Results from a phase IIa study evaluating Simeprevir and Sofosbuvir in prior null responder Hepatitis C patients have been presented at CROI. 6 March 2013. Archived 16 October 2012 at the Wayback Machine
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