Grazoprevir

    Grazoprevir/elbasvir is an investigational, once-daily single tablet regimen consisting of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A replication complex inhibitor). As part of Merck’s broad clinical trials program, grazoprevir/elbasvir is being studied in multiple HCV genotypes and in patients with difficult-to-treat conditions such as HIV/HCV co-infection, advanced chronic kidney disease, inherited blood disorders, liver cirrhosis and those on opiate substitution therapy.

    [td_text_with_title custom_title=”Latest post”]
    Merck

    EMA accepts marketing application for Grazoprevir

    KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the European Medicines Agency (EMA) has accepted for review a marketing authorization application (MAA) for grazoprevir/elbasvir (100mg/50mg), an investigational, once-daily, single-tablet combination therapy for the treatment of adult patients with chronic hepatitis C (HCV) genotypes (GT) 1, 3, 4 or […]

    0 comments
    Merck

    Merck files NDA for Grazoprevir

    On April 8, 2015, the company announced that the U.S. Food and Drug Administration (FDA) had granted Breakthrough Therapy designation to grazoprevir/elbasvir for the treatment of patients infected with chronic HCV GT1 with end-stage renal disease on hemodialysis and patients infected with chronic HCV GT4. The 28th of May Merck filed a New Drug Application. 

    0 comments
    [/td_text_with_title][td_text_with_title custom_title=”From Wikipedia”]
    Grazoprevir
    Grazoprevir.svg
    Clinical data
    Trade names Zepatier (combination with elbasvir)
    Synonyms MK-5172
    License data
    Routes of
    administration
    Oral
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Protein binding 98.8%
    Metabolism CYP3A4
    Biological half-life 31 hours
    Excretion >90% via faeces, <1% via urine
    Identifiers
    CAS Number
    PubChem CID
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    Chemical and physical data
    Formula C38H50N6O9S
    Molar mass 766.901 g/mol
    3D model (JSmol)

    Grazoprevir is a drug[1] 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.[2]

    Grazoprevir is a second generation hepatitis C virus protease inhibitor acting at the NS3/4A protease targets.[3] It has good activity against a range of HCV genotype variants, including some that are resistant to most currently used antiviral medications.[4][5]

    Side effects

    Side effects have only be assessed in the combination with elbasvir; see Elbasvir/grazoprevir#Side effects.

    Interactions

    Grazoprevir is transported by the solute carrier proteins SLCO1B1 and SLCO1B3. Drugs that inhibit this proteins, such as rifampicin, ciclosporin, and a number of AIDS medications (atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cobicistat), can cause a significant increase in grazoprevir blood plasma levels. The substance is degraded by the liver enzyme CYP3A4. Combination with drugs that induce this enzyme, such as efavirenz, carbamazepine or St. John's wort, can lead to ineffectively low plasma levels of grazoprevir. Combination with CYP3A4 inhibitors may increase plasma levels.[6][7]

    Pharmacology

    Mechanism of action

    Grazoprevir blocks NS3, a serine protease enzyme the virus needs for splitting its polyprotein into the functional virus proteins, and NS4A, a cofactor of NS3.[6]

    Pharmacokinetics

    Grazoprevir reaches peak plasma concentrations two hours after oral intake together with elbasvir (variation between patients: 30 minutes to three hours). In hepatitis C patients, steady state concentrations are found after about six days. Plasma protein binding is 98.8%, mainly to albumin and alpha-1-acid glycoprotein. Part of the substance is oxidised in the liver, largely by the enzyme CYP3A4. The biological half-life is 31 hours on average. Over 90% are excreted via the faeces, and less than 1% via the urine.[6]

    References

    1. ^ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm483828.htm
    2. ^ Lawitz E, Gane E, Pearlman B, Tam E, Ghesquiere W, Guyader D, Alric L, Bronowicki JP, Lester L, Sievert W, Ghalib R, Balart L, Sund F, Lagging M, Dutko F, Shaughnessy M, Hwang P, Howe AY, Wahl J, Robertson M, Barr E, Haber B. Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial. Lancet. 2015;385(9973):1075-86. doi: 10.1016/S0140-6736(14)61795-5. PMID 25467591
    3. ^ Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, Koch U, Petrocchi A, Holloway MK, Butcher JW, Romano JJ, Bush KJ, Gilbert KF, McIntyre CJ, Nguyen KT, Nizi E, Carroll SS, Ludmerer SW, Burlein C, DiMuzio JM, Graham DJ, McHale CM, Stahlhut MW, Olsen DB, Monteagudo E, Cianetti S, Giuliano C, Pucci V, Trainor N, Fandozzi CM, Rowley M, Coleman PJ, Vacca JP, Summa V, Liverton NJ. Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor. ACS Med Chem Lett. 2012;3(4):332-6. doi: 10.1021/ml300017p. PMID 24900473
    4. ^ Summa V, Ludmerer SW, McCauley JA, Fandozzi C, Burlein C, Claudio G, Coleman PJ, Dimuzio JM, Ferrara M, Di Filippo M, Gates AT, Graham DJ, Harper S, Hazuda DJ, Huang Q, McHale C, Monteagudo E, Pucci V, Rowley M, Rudd MT, Soriano A, Stahlhut MW, Vacca JP, Olsen DB, Liverton NJ, Carroll SS. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother. 2012;56(8):4161-7. doi: 10.1128/AAC.00324-12. PMID 22615282
    5. ^ Gentile I, Buonomo AR, Borgia F, Zappulo E, Castaldo G, Borgia G. MK-5172 : a second-generation protease inhibitor for the treatment of hepatitis C virus infection. Expert Opinion on Investigational Drugs. 2014;23(5):719-28. doi: 10.1517/13543784.2014.902049. PMID 24666106
    6. ^ a b c Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. 
    7. ^ FDA Professional Drug Information on Zepatier.
    source: https://en.wikipedia.org/wiki/Grazoprevir[/td_text_with_title]