Grazoprevir

Grazoprevir
Clinical data
Trade names	Zepatier (combination with elbasvir)
Other names	MK-5172
License data	EU EMA: by INN;
Routes of; administration	Oral
ATC code	J05AX68 (WHO) (combination with elbasvir);
Legal status
Legal status	US: ℞-only;
Pharmacokinetic data
Protein binding	98.8%
Metabolism	CYP3A4
Elimination half-life	31 hours
Excretion	>90% via faeces, <1% via urine
Identifiers
	IUPAC name (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	1350514-68-9;
PubChem CID	44603531;
DrugBank	DB11575;
ChemSpider	28506694;
UNII	8YE81R1X1J;
KEGG	D10639;
ChEBI	CHEBI:132975 ;
CompTox Dashboard (EPA)	DTXSID50159234 ;
Chemical and physical data
Formula	C38H50N6O9S
Molar mass	766.901 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C1C(C(C)(C)C)NC(=O)OC3CC3CCCCCc2nc4ccc(OC)cc4nc2OC(C6)CN1C6C(=O)NC5(CC5C=C)C(=O)NS(=O)(=O)C7CC7;
	InChI 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;

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

^ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm483828.htm
^ 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
^ 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
^ 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
^ 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
^ ^a ^b ^c Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
^ FDA Professional Drug Information on Zepatier.

[1] ttp://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

[AC-6] Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.

[7] FDA Professional Drug Information on Zepatier.

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