Grazoprevir

Drug approved for the treatment of hepatitis C From Wikipedia, the free encyclopedia

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]

Trade namesZepatier (combination with elbasvir)
Other namesMK-5172
License data
Routes of
administrationOral
Quick facts Clinical data, Trade names ...
Grazoprevir
Clinical data
Trade namesZepatier (combination with elbasvir)
Other namesMK-5172
License data
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding98.8%
MetabolismCYP3A4
Elimination half-life31 hours
Excretion>90% via faeces, <1% via urine
Identifiers
  • (1R,18R,20R,24S,27S)-N-{(1R,2S)-1-[(Cyclopropylsulfonyl)carbamoyl]-2-vinylcyclopropyl}-7-methoxy-24-(2-methyl-2-propanyl)-22,25-dioxo-2,21-dioxa-4,11,23,26-tetraazapentacyclo[24.2.1.03,12.05,10.0 18,20]nonacosa-3,5,7,9,11-pentaene-27-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC38H50N6O9S
Molar mass766.91 g·mol−1
3D model (JSmol)
    • O=C1[C@@H](NC(O[C@H]2C[C@H]2CCCCCC3=NC4=CC=C(C=C4N=C3O[C@@H]5C[C@@H](C(N[C@]6(C(NS(=O)(C7CC7)=O)=O)C[C@H]6C=C)=O)N1C5)OC)=O)C(C)(C)C
    • InChI=1S/C38H50N6O9S/c1-6-22-19-38(22,35(47)43-54(49,50)25-13-14-25)42-32(45)29-18-24-20-44(29)34(46)31(37(2,3)4)41-36(48)53-30-16-21(30)10-8-7-9-11-27-33(52-24)40-28-17-23(51-5)12-15-26(28)39-27/h6,12,15,17,21-22,24-25,29-31H,1,7-11,13-14,16,18-20H2,2-5H3,(H,41,48)(H,42,45)(H,43,47)/t21-,22-,24-,29+,30-,31-,38-/m1/s1
    • Key:OBMNJSNZOWALQB-NCQNOWPTSA-N
    Close

    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

    Main article: Elbasvir/grazoprevir § Side effects

    Side effects have only been assessed in the combination with elbasvir. Common side effects of the combination include feeling tired, nausea, reduced appetite, and headache. Low red blood cell count has occurred when co-administered with ribavirin in some cases.[6][7] The most important risks are alanine transaminase elevation, hyperbilirubinemia, drug resistance development and drug interactions.[8]

    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.[7][9]

    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.[7]

    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.[7]

    References

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