Randomized Study of Asunaprevir plus Pegylated Interferon-α and Ribavirin for Previously Untreated Genotype 1 Chronic Hepatitis C

Bronowicki, Jean Pierre; Pol, Stanislas; Thuluvath, Paul J.; Larrey, Dominique; Martorell, Claudia; Rustgi, Vinod K.; Morris, David W.; Younes, Ziad; Fried, Michael; Bourlière, Marc; Hézode, Christophe; Reddy, K. Rajender; Massoud, Omar; Abrams, Gary A.; Ratziu, Vlad; He, Bing; Eley, Timothy; Ahmad, Alaa; Cohen, David E.; Hindes, R.; McPhee, Fiona; Reilly, Bridget; Méndez, Patricia; Hughes, Eric

doi:10.3851/imp2660

Cited by 45 publications

(37 citation statements)

References 20 publications

(27 reference statements)

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“…In the initial phase 2 study in combination with peginterferon alfa/ribavirin (study AI447-016), the phase 2 (tablet) dose of asunaprevir was reduced from 600 mg once or twice daily to 200 mg twice daily because of grade 3-4 ALT and AST elevations, which demonstrated an association with systemic exposure of asunaprevir [34]. Asunaprevir was also studied in phase 2 in North American/European subjects and Japanese subjects in combination with the NS5A inhibitor daclatasvir with or without peginterferon alfa/ribavirin [35][36][37].…”

Section: Optimization Of Asunaprevir Dosing Regimenmentioning

confidence: 99%

Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug–Drug Interactions

Eley

Garimella

et al. 2015

Clin Pharmacokinet

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Asunaprevir is a tripeptidic acylsulfonamide inhibitor of the hepatitis C virus (HCV) NS3/4A protease. Asunaprevir undergoes rapid absorption, with a time to reach maximum plasma concentration (T max) of 2-4 h and an elimination half-life (t ½) of ≈15-20 h observed in single-ascending dose studies. Steady state was achieved by day 7 in multiple-ascending dose studies. The large food effect observed with earlier formulations was mitigated by the soft-gel capsule. Asunaprevir demonstrates high apparent oral clearance and minimal renal elimination, and is eliminated primarily via cytochrome P450 (CYP) 3A4-mediated hepatic oxidative metabolism and faecal excretion. Highly preferential distribution of asunaprevir to the liver occurs via organic anion-transporting polypeptide (OATP)-mediated transport and results in low plasma concentrations. The condition of the liver affects disposition, as higher asunaprevir plasma exposures are observed in patients infected with HCV and/or hepatic impairment. Japanese patients also have higher exposure relative to North American/European patients, but comparable safety at the registrational dose. Asunaprevir has a low potential to perpetrate drug-drug interactions via CYP3A4, P-glycoprotein and OATP, but is a moderate CYP2D6 inhibitor; concomitant drugs that are substrates of CYP2D6 or P-glycoprotein and have a narrow therapeutic index should be used with care. Asunaprevir plasma exposure is strongly affected by inhibitors of OATP transport. No clinically significant interactions were observed between asunaprevir and daclatasvir or daclatasvir/beclabuvir. Asunaprevir has a complex pharmacokinetic profile and forms part of potent and well-tolerated all-oral regimens for the treatment of chronic HCV infection.

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Section: Optimization Of Asunaprevir Dosing Regimenmentioning

confidence: 99%

Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug–Drug Interactions

Eley

Garimella

et al. 2015

Clin Pharmacokinet

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“…44 Asunaprevir is a twice daily protease inhibitor that was assessed in a phase IIa study of 47 treatment naive patients with GT1 HCV at three doses with peginterferon-ribavirin for 48 weeks; those treated with asunaprevir achieved sustained virologic response rates at 24 weeks of 83-92%. 45 Vaniprevir, another twice daily protease inhibitor, when given with peginterferon-ribavirin in a short four week lead in, followed by 44 weeks of peginterferon-ribavirin alone, achieved sustained virologic response rates at 24 weeks of 61-84% in 94 treatment naive patients with GT1 HCV. However, more gastrointestinal, side effects such as nausea, vomiting, and diarrhea, were seen in the vaniprevir treated group.…”

Section: Interferon-free Regimens (Table 3)mentioning

confidence: 99%

Antiviral treatment of hepatitis C

Feeney

Chung

2014

BMJ

185

152

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Hepatitis C virus (HCV) infection is a substantial health problem worldwide. Most patients infected with HCV remain chronically infected, with an increased risk of cirrhosis and hepatocellular carcinoma. Although they are associated with toxicities and low sustained viral response rates, interferon alfa and ribavirin have been the mainstay of treatment until recently. New direct acting antivirals, specifically designed to inhibit three viral proteins (the NS3/4A protease, the NS5A protein, and the NS5B RNA dependent RNA polymerase) are now becoming available. The NS3/4A inhibitor simeprevir and NS5B inhibitor sofosbuvir have recently been licensed and can reduce the length of antiviral treatment, improve response rates, and allow for interferon-free regimens for some HCV genotypes. Several other newer direct acting antivirals have shown promise in clinical studies and are likely to be licensed soon. These agents seem to facilitate the use of shortened courses of combination interferon-free therapy, which are associated with high (>95%) sustained response rates and relatively few toxicities. These regimens have also been successful in patients who were previously difficult to treat, including those with cirrhosis, HIV coinfection, and those who have undergone liver transplantation. The high cost of these agents may be the biggest challenge to their implementation worldwide.

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“…Efficacy has been tested with P/R in a phase IIa study on G1 with an SVR of 83-92% [18]. The drug has been further developed within IFN-free regimens, after encouraging results of the phase II in G1b [19,20 ] Safety issues are related to elevations in ALT which were mainly observed with high doses but are rare using the current dose of 200 mg bid (1-3% grade 3-4).…”

Section: Asunaprevir (Formerly Bms-650032)mentioning

confidence: 98%

Treatment of HCV infection with the novel NS3/4A protease inhibitors

Luca

Bianco

Rossetti

2014

Current Opinion in Pharmacology

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Randomized Study of Asunaprevir plus Pegylated Interferon-α and Ribavirin for Previously Untreated Genotype 1 Chronic Hepatitis C

Abstract: Asunaprevir plus PEG-IFN and ribavirin achieved higher response rates than placebo plus PEG-IFN and ribavirin, with a tolerable adverse event profile at the 200 mg twice-daily dose. This dose is being evaluated in the Phase IIb and Phase III studies.

Cited by 45 publications

References 20 publications

Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug–Drug Interactions

Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug–Drug Interactions

Antiviral treatment of hepatitis C

Treatment of HCV infection with the novel NS3/4A protease inhibitors

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