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Current Medicinal Chemistry
ISSN (Print): 0929-8673
ISSN (Online): 1875-533X
VOLUME: 21
ISSUE: 28
DOI: 10.2174/0929867321666140706125950      Price:  $58









ABT-450: A Novel Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

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Author(s): Ivan Gentile, Federico Borgia, Antonio Riccardo Buonomo, Emanuela Zappulo, Giuseppe Castaldo and Guglielmo Borgia
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Pages 3261-3270 (10)
Abstract:
About 2.3% of the world’s population is infected with hepatitis C virus (HCV) and patients have a high risk of developing liver cirrhosis and its complications. Current therapeutic strategies are based on a combination of pegylatedinterferon, ribavirin and (only for patients with genotype 1 infection) a protease inhibitor (boceprevir or telaprevir). Consequently, all these combinations have the limitations of interferon. In fact, they are contraindicated in decompensated disease and in subjects with severe comorbidities, and are associated with a high rate of side effects. Moreover, they are poorly effective in advanced disease. As complete viral eradication is associated with improved disease-free survival, several molecules are under clinical development for their potential to overcome the drawbacks of currently available treatments. This review focuses on the pharmacodynamics, pharmacokinetics, safety and tolerability of ABT-450, a potent inhibitor of non-structural 3 protease. ABT-450 is a substrate of cytochrome P450; hence its co-administration with ritonavir, a cytochrome P450 inhibitor, dramatically increases the plasma concentration and half-life of ABT-450 and allows once-daily administration. Given in monotherapy for 3 days at different doses, ABT-450 causes a mean maximum viral decline of about 4 logs. Interestingly, high doses of ABT-450 are associated with a reduced and delayed development of resistance-conferring mutations. Given in combination with other direct antiviral drugs, the sustained response rate reaches 90-95% in both naïve and treatment-experienced genotype 1 patients, and tolerability is good. In conclusion, ABT-450 is an excellent component of interferon-free combinations for the treatment of chronic HCV infection.
Keywords:
ABT-072, ABT-267, ABT-333, ABT-450, HCV, pegylated-interferon, resistance, ribavirin, ritonavir.
Affiliation:
Department of Clinical Medicine and Surgery (Ed. 18) – University of Naples “Federico II”, via S. Pansini 5, I-80131 Naples, Italy.