Boceprevir
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| Non-proprietary name | Boceprevir | |||||||||||||||||||||
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(1 R , 2 S , 5 S ) - N - [(2Ξ) -4-Amino-1-cyclobutyl-3,4-dioxobutan-2-yl] -3 - {(2 S ) -2 - [( tert -butylcarbamoyl) amino] -3,3-dimethylbutanoyl} -6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide ( IUPAC ) |
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| Molecular formula | C 27 H 45 N 5 O 5 | |||||||||||||||||||||
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| Molar mass | 519.7 g · mol -1 | |||||||||||||||||||||
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poorly soluble in water, readily soluble in methanol , ethanol and isopropanol |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | ||||||||||||||||||||||
Boceprevir is a virus-inhibiting ( virostatic ) drug and the first representative of the new substance class of HCV protease inhibitors (“first in class drug”) to be used as such .
As Victrelis ® (pharmaceutical company: MSD Sharp & Dohme ), boceprevir was approved in the USA in May 2011 and in the EU in July 2011 for the treatment of chronic hepatitis C virus infection , exclusively in combination with the two active substances peginterferon alfa and ribavirin , approved for adults. MSD has announced that it will cease marketing Victrelis ® in the US at the end of 2015.
Boceprevir is effective orally .
Mechanism of action
Boceprevir inhibits the viral NS3 protease of the hepatitis C virus (HCV) genotype 1 by binding covalently but reversibly to the serine group (Ser139) in the active site of the protease. The formation of the viral proteins by breaking down the viral polyprotein that is primarily formed is thereby prevented at the point of cleavage of the non-structural protein 3 (NS3) and virus replication in HCV-infected host cells is blocked.
The combination with the two standard drugs peginterferon alfa and ribavirin is intended to prevent the development of resistance .
application areas
Boceprevir in combination with peginterferon alfa and ribavirin is indicated for the treatment of genotype 1 hepatitis C virus infection in adult patients with compensated liver disease who have either received no treatment, have not responded to treatment, or have relapsed to have. Compensated liver disease is when the liver is damaged but still functions normally.
The effectiveness of Victrelis has been demonstrated in two placebo-controlled phase III studies in which 1099 untreated (SPRINT-2 study) and 404 previously unsuccessful patients (RESPOND-2 study) with chronic infection with genotype 1 hepatitis C and compensated liver disease participated . All patients also received peginterferon alfa and ribavirin. The main measure of effectiveness was the number of patients who had no virus in their blood 24 weeks after the end of treatment ( sustained virological response , SVR) and who were therefore considered cured.
In both studies, adding boceprevir for 44 weeks to the current standard therapy with peginterferon alfa and ribavirin resulted in a significantly higher sustained virological response (66% in first-time patients, 67% in unsuccessful pretreated patients) compared to standard therapy alone (38% in first-time treated patients, 21% in unsuccessfully pretreated patients).
Restrictions on use and side effects
The combination boceprevir / peginterferon alfa / ribavirin is contraindicated in patients with hypersensitivity to one of the active substances, in patients with autoimmune hepatitis and during pregnancy. Since boceprevir is a potent inhibitor of CYP3A4 / A5 , its use is also contraindicated in concomitant use of drugs whose clearance is highly dependent on the same enzyme system and in which elevated plasma concentrations can have serious or life-threatening consequences.
A number of side effects can occur with the combination therapy boceprevir / peginterferon alfa / ribavirin, the most common of which are fatigue, anemia , nausea, headache and taste disorders ( dysgeusia ).
The simultaneous use of boceprevir with certain ritonavir- boosted HIV protease inhibitors can lead to interactions which manifest themselves in decreased plasma levels .
chemical characterization
The synthetically produced substance boceprevir has five chiral centers, four of which have a fixed configuration. At the third carbon atom, calculated from the ketoamide end of the molecule, however, the substituents can adopt an (R) or (S) configuration. The drug is a mixture of the two diastereomeric forms in a ratio of about 1: 1.
The (S) isomer (diastereomer SCH534128) is the pharmacologically active form, which inhibits the NS3 protease of the hepatitis C virus by a factor of 41 to 130 times more than the (R) isomer (diastereomer SCH534129). In-vitro studies indicate that both forms mutually merge (epimerize) in the plasma. In vivo, depending on the species, there are different equilibria of the plasma levels (e.g. the ratio SCH534128: SCH534129 in equilibrium in mice is approx. 1.2: 1, in rats approx. 1: 1, in monkeys approx. 1: 5 .9 and in humans approx. 2.2: 1).
Boceprevir is an amorphous powder that is difficult to wet with water and which also dissolves poorly in water. Since boceprevir does not form ionic forms, its solubility is pH independent. Boceprevir is readily soluble in methanol , ethanol and isopropanol .
Early benefit assessment
In the context of Section 35a SGB V ( AMNOG ) ( early benefit assessment ), the Federal Joint Committee (G-BA) in 2012 saw an indication of a non-quantifiable additional benefit for boceprevir compared to the ACT, both for therapy-naive and therapy-experienced patients. It did not follow the previous assessment by the Institute for Quality and Efficiency in Health Care (IQWiG) , which saw an additional benefit only for some of the patient groups examined.
swell
- Information on Victrelis on the European Medicines Agency website
Individual evidence
- ↑ a b Assessment report, Victrelis (PDF; 1.9 MB), Committee for Medicinal Products for Human Use , August 3, 2011.
- ↑ American specialist information on Victrelis, May 2005. ( Memento of the original from November 12, 2011 in the Internet Archive ) Info: The archive link has been inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. (English; PDF; 444 kB).
- ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
- ↑ http://blogs.wsj.com/pharmalot/2015/01/21/merck-will-no-longer-sell-its-victrelis-hepatitis-c-drug-in-the-us/ .
- ↑ Entry on boceprevir. In: Römpp Online . Georg Thieme Verlag, accessed on June 27, 2019.
- ↑ Rote-Hand-Brief dated February 23, 2012 on possible drug interactions (PDF; 120 kB) retrieved from the website of the Drugs Commission of the German Medical Association (AkdÄ).
- ↑ Health Canada: Summary Basis of Decision (SBD) for VICTRELIS ( Memento of the original from January 11, 2013 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. , Judgment by the Canadian Authority for the Decree 22nd 2011 approval decision.
- ↑ Information archive | Early benefit assessment (§ 35a SGB V) , website of the Federal Joint Committee (G-BA).
- ↑ Resolution: Reference to an additional benefit of boceprevir (PDF; 307 kB), Federal Joint Committee (G-BA).
- ↑ boceprevir: indication of added benefit for certain patients ; Accessed March 26, 2020.
