Grazoprevir Explained

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 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.

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.

Notes and References

  1. Web site: FDA approves Zepatier for treatment of chronic hepatitis C genotypes 1 and 4. . 2018-11-03.
  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 . 6 . 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 . 385 . 9973 . 1075–86 . March 2015 . 25467591 . 10.1016/S0140-6736(14)61795-5 .
  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 . 6 . Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor . ACS Medicinal Chemistry Letters . 3 . 4 . 332–6 . April 2012 . 24900473 . 4025840 . 10.1021/ml300017p .
  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 . 6 . MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants . Antimicrobial Agents and Chemotherapy . 56 . 8 . 4161–7 . August 2012 . 22615282 . 3421554 . 10.1128/AAC.00324-12 .
  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 . 23 . 5 . 719–28 . May 2014 . 24666106 . 10.1517/13543784.2014.902049 . 207477059 .
  6. Web site: ZEPATIER (elbasvir and grazoprevir) Tablets, for Oral Use. Full Prescribing Information. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.. 31 January 2016.
  7. Book: Austria-Codex. Haberfeld H . Österreichischer Apothekerverlag . Vienna . 2015 . German.
  8. Web site: European Public Assessment Report. European Medicines Agency. 16 December 2017. 18 December 2017. https://web.archive.org/web/20171218225330/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004126/WC500211237.pdf. dead.
  9. on Zepatier.

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