|Metabolism||Extensive hepatic through oxidation, reduction and N-dealkylation (CYP3A4)|
|Excretion||Feces (81.1%), urine (3.14%)|
|Chemical and physical data|
|Molar mass||g·mol−1 707.97|
|3D model (JSmol)|
Narlaprevir (trade name Arlansa, codenamed SCH 900518), is an inhibitor of NS3/4A serine protease, intended for the treatment of chronic hepatitis C caused by genotype 1 virus) in combination with other antiviral drugs.
Mechanism of action
Narlaprevir is an oral NS3 serine protease inhibitor of hepatitis C virus. It inhibits viral replication in infected host cells. The mechanism of inhibition involves reversible covalent binding of narlaprevir with NS3 protease active site via the ketoamide functional group.
Treatment of chronic hepatitis C virus (HCV) infection genotype 1 in combination with ritonavir, pegylated interferon alfa and ribavirin, in patients older than 18 years with compensated liver disease who are treatment-naïve or have failed dual combination of pegylated interferon alfa and ribavirin. Narlaprevir cannot be used as a single agent.
- pregnancy or lactation
- children up to 18 years of age
- severe neutropenia
- liver failure
- prior treatment with HCV protease inhibitors
- lactase deficiency, lactose intolerance, glucose-galactose malabsorption.
H. Reesink et al. (2009) demonstrated narlaprevir safety and antiviral activity both as a single agent and in dual combination with pegylated interferon alfa-2b.
In the year 2016 a large-scale phase III multicenter PIONEER study was completed. Sustained virologic response (SVR) was 89% in treatment-naïve and 70% in treatment-experienced patients 24 weeks after the end of treatment in the narlaprevir group, whereas in the control group SVR was only 59.6% in treatment-naïve and 24.5% in treatment-experienced patients on dual therapy with pegylated interferon alfa and ribavirin. Adding narlaprevir to dual therapy with pegylated interferon alfa and ribavirin did not affect narlaprevir safety profile. A phase I study of narlaprevir pharmacokinetics in combination with ritonavir in patients with compensated cirrhosis was also completed (Liver Meeting AASLD, 13–17 February 2015, San Francisco, California, USA).
According to professor I.G. Bakulin, the head of the Department of Hepatology of the Moscow clinical research center and chief gastroenterologist of Moscow government healthcare department, the regulatory approval of narlaprevir has become a major milestone accomplished in the fight against hepatitis C in Russia.
In 2012, the pharmaceutical group R-Pharm acquired a license to manufacture narlaprevir from the Merck & Co. (MSD). Further development of the drug was conducted by R-Pharm in cooperation with Texas Liver Institute (USA), with the support of the Federal Target Program "Development of the Pharmaceutical and Medical Industry of the Russian Federation for the period up to 2020 and beyond". About 700 million rubles were invested in clinical trials and the development of the drug, of which 120 million rubles came from the Russian Government.
The drug is manufactured at a pharmaceutical factory in the Russian city of Yaroslavl.
- "Russian State Registry of Medicines. Arlansa (narlaprevir) film-coated tablets: Registration sertificate" (in Russian). Retrieved 11 January 2017.
- Tong, X; Arasappan, A; Bennett, F; Chase, R; Feld, B; Guo, Z; Hart, A; Madison, V; Malcolm, B; Pichardo, J; Prongay, A; Ralston, R; Skelton, A; Xia, E; Zhang, R; Njoroge, FG (June 2010). "Preclinical Characterization of the Antiviral Activity of SCH 900518 (Narlaprevir), a Novel Mechanism-Based Inhibitor of Hepatitis C Virus NS3 Protease". Antimicrobial Agents and Chemotherapy. 54 (6): 2365–70. doi:10.1128/AAC.00135-10. PMC 2876368. PMID 20308381.
- Chen, KX; Njoroge, FG (2012). "12. Discovery of Boceprevir and Narlaprevir: The First and Second Generation of HCV NS3 Protease Inhibitors". In Huang, X; Aslanian, RG. Case Studies in Modern Drug Discovery and Development. Oxford: John Wiley & Sons, Inc. pp. 296–335. doi:10.1002/9781118219683.ch12. ISBN 9781118219683.
- "Российский препарат от гепатита С готовится к выпуску" (in Russian). Собеседник.RU. 30 June 2016.
- Wang, H; Geng, L; Chen, BZ; Ji, M (October 2014). "Computational Study on the Molecular Mechanisms of Drug Resistance of Narlaprevir Due to V36M, R155K, V36M+R155K, T54A, and A156T Mutations of HCV NS3/4A Protease". Biochemistry and Cell Biology. 92 (5): 357–69. doi:10.1139/bcb-2014-0039. PMID 25178998.
- Rudakova, AV; Gusev, DA; Uskov, AN; Konovalova, LN; Lobzin, YV (2016). "Cost-Effectiveness of the Second Wave of Protease Inhibitors in the Treatment of Chronic Hepatitis C (Genotype 1) in Patients Not Previously Treated with Antiviral Drugs, and for Relapsed Disease". Journal of Infectology (in Russian). 8 (1): 79–82. doi:10.22625/2072-6732-2016-8-1-79-82 (inactive 2019-01-30).
- Arasappan, A; Bennett, F; Bogen, SL; Venkatraman, S; Blackman, M; Chen, KX; Hendrata, S; Huang, Y; Huelgas, RM; Nair, L; Padilla, AI; Pan, W; Pike, R; Pinto, P; Ruan, S; Sannigrahi, M; Velazquez, F; Vibulbhan, B; Wu, W; Yang, W; Saksena, AK; Girijavallabhan, V; Shih, NY; Kong, J; Meng, T; Jin, Y; Wong, J; McNamara, P; Prongay, A; Madison, V; Piwinski, JJ; Cheng, KC; Morrison, R; Malcolm, B; Tong, X; Ralston, R; Njoroge, FG (13 May 2010). "Discovery of Narlaprevir (SCH 900518): A Potent, Second Generation HCV NS3 Serine Protease Inhibitor". ACS Medicinal Chemistry Letters. 1 (2): 64–69. doi:10.1021/ml9000276. PMC 4007962. PMID 24900178.
- Bakulin, I. "The "Second Wave" PI Narlaprevir in Russian Patients with Genotype 1 Chronic Hepatitis C" (PDF).
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|url=value (help) (PDF) (in Russian). p. 20.
- Dranishnikova, M; Fomchenko, D (21 June 2012). "Together Against Hepatitis" (in Russian). Vedomosti.
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- Nevinnaya, I. "Minpromtorg Supports the Development of New Drugs" (in Russian) (Federal Issue №5823 (150)). Rossiyskaya Gazeta.
- Burnevish, EZ; Tikhonova, NY; Schanitsyna, SE (2014). "Narlaprevir, Boosted with Ritonavir, in Combination with Pegylated Interferon Alpha-2A and Ribavirin in the Treatment of Chronic Hepatitis C". Clinical Pharmacology and Therapy. 5: 34–9.