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]
Contents
1Side effects
2Interactions
3Pharmacology
3.1Mechanism of action
3.2Pharmacokinetics
4References
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
^"FDA approves Zepatier for treatment of chronic hepatitis C genotypes 1 and 4". 2018-11-03.
^Lawitz E, Gane E, Pearlman B, Tam E, Ghesquiere W, Guyader D, et al. (March 2015). "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. doi:10.1016/S0140-6736(14)61795-5. PMID 25467591.
^Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, et al. (April 2012). "Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor". ACS Medicinal Chemistry Letters. 3 (4): 332–6. doi:10.1021/ml300017p. PMC 4025840. PMID 24900473.
^Summa V, Ludmerer SW, McCauley JA, Fandozzi C, Burlein C, Claudio G, et al. (August 2012). "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. doi:10.1128/AAC.00324-12. PMC 3421554. PMID 22615282.
^Gentile I, Buonomo AR, Borgia F, Zappulo E, Castaldo G, Borgia G (May 2014). "MK-5172 : a second-generation protease inhibitor for the treatment of hepatitis C virus infection". Expert Opinion on Investigational Drugs. 23 (5): 719–28. doi:10.1517/13543784.2014.902049. PMID 24666106.
^"ZEPATIER (elbasvir and grazoprevir) Tablets, for Oral Use. Full Prescribing Information" (PDF). Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Retrieved 31 January 2016.
…tablet consists of 50 mg elbasvir and 100 mg grazoprevir and is administered once daily with or without food. Prior to administration of elbasvir-grazoprevir, patients with genotype 1a infection should …
… Elbasvir-grazoprevir plus weight-based ribavirin (daily dose 1000 mg for those <75 kg and 1200 mg for those ≥75 kg) is also effective for such protease-inhibitor failures . Although grazoprevir is also …
…included with UpToDate. Elbasvir and grazoprevir are available only as a fixed-dose combination. Both are primarily metabolized through CYP3A metabolism, and grazoprevir is a substrate of OATP1B1/3 …
…patients with Child Pugh classes B and C cirrhosis. Elbasvir-grazoprevir – For genotype 4 infection, the fixed-dose combination pill elbasvir-grazoprevir is given once daily for 12 weeks for treatment-naive …
… more significant for regimens that contain HCV protease inhibitors (eg, simeprevir, paritaprevir, grazoprevir) but affect use of all direct-acting antiviral agents. Potential drug interactions with specific …
English Journal
Elbasvir/grazoprevir treatment in an HCV-infected peritoneal dialysis patient.
Chen J, Li Y, Li G, Lei P.
Renal failure. 2020 Nov;42(1)377-380.
Hepatitis C virus (HCV) infection is known to affect long-term patient survivals. Elbasvir/grazoprevir (EBR/GZR) has shown a high cure rate in hemodialysis patients with HCV infection. However, the combination is rarely used in peritoneal dialysis patients. Herein, we report a case of successful tre
Modeling-based response-guided therapy for chronic hepatitis C under glecaprevir/pibrentasvir may identify patients for ultra-short treatment duration.
Dasgupta S, Imamura M, Gorstein E, Nakahara T, Tsuge M, Churkin A, Yardeni D, Etzion O, Uprichard SL, Barash D, Cotler SJ, Dahari H, Chayama K.
The Journal of infectious diseases. 2020 May;().
We recently showed in a proof-of-concept study that real-time modeling-based response-guided therapy (RGT) can shorten hepatitis C virus (HCV) treatment duration with sofosbuvir/velpatasvir, elbasvir/grazoprevir and sofosbuvir/ledipasvir without compromising efficacy, confirming our retrospective mo
Real-world experience of elbasvir/grazoprevir in Taiwan: This study was focused on liver and renal adverse effects.
Hsieh YC, Lin CL, Hung CH, Chen CH, Tung SY, Lin CY, Hu TH, Lu SN, Chien RN, Sheen IS.
Journal of viral hepatitis. 2020 May;27(5)505-513.
Elbasvir/grazoprevir with or without ribavirin has excellent efficacy and safety for the treatment of hepatitis C virus (HCV) genotype 1 and 4 patients. The real-world experience has been reported but the detailed analysis of liver and renal adverse effects is lacking. This study evaluated the real-
… <p>The aim of this retrospective multicenter study was to clarify efficacy and safety of Elbasvir/Grazoprevir for chronic hepatitis C patients with chronic kidney disease (CKD). … Forty-five patients with CKD were administered Elbasvir/Grazoprevir and subjected to this analysis. … This study suggests that Elbasvir/Grazoprevir therapy is effective and safe for genotype 1b chronic hepatitis C patients with CKD.</p> …
Grazoprevir anhydrous is a Hepatitis C Virus NS3/4A Protease inhibitor with IC50 values of 7pM, 4pM, and 62pM for HCV genotype 1a, 1B, and 4 respectively. 体外試験 MK-5172 is a novel P2-P4 quinoxaline macrocyclic NS3/4a ...
Grazoprevir is a direct acting antiviral medication used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is ...