Treatment of chronic hepatitis C patients with the NS3/4A protease inhibitor danoprevir (ITMN-191/RG7227) leads to robust reductions in viral RNA: A phase 1b multiple ascending dose study

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• 作者：Nicole Forestier¹ ; ^{nicole.forestier@kgu.de"" rel=""nofollow} ; ^{forestier@med.uni-frankfurt.de"" rel=""nofollow} ; Dominique Larrey² ; Dominique Guyader³ ; Patrick Marcellin⁴ ; Ré ; gine Rouzier⁵ ; Alain Patat⁶ ; Patrick Smith⁷ ; Williamson Bradford⁸ ; Steven Porter⁸ ; Lawrence Blatt⁸ ; Scott D. Seiwert⁸ ; Stefan Zeuzem¹
• 关键词：HCV ; Direct antiviral ; Protease inhibitor ; ITMN-191 ; Danoprevir
• 刊名：Journal of Hepatology
• 出版年：2011
• 出版时间：June 2011
• 年：2011
• 卷：54
• 期：6
• 页码：1130-1136
• 全文大小：651 K

文摘

Background & Aims

Danoprevir is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. The present study assessed the safety, pharmacokinetics, and antiviral activity of danoprevir in a randomized, placebo-controlled, 14-day multiple ascending dose study in patients with chronic HCV genotype 1 infection.

Methods

Four cohorts of treatment-naïve (TN) patients (100 mg q12 h, 100 mg q8 h, 200 mg q12 h, 200 mg q8 h) and one cohort of non-responders (NR) to prior pegylated interferon alfa-ribavirin treatment (300 mg q12 h) were investigated.

Results

Danoprevir was safe and well tolerated; adverse events were generally mild, transient and were not associated with treatment group or dose level. Danoprevir displayed a slightly more than proportional increase in exposure with increasing daily dose and was rapidly eliminated from the plasma compartment. Maximal decreases in HCV RNA were: −3.9 log₁₀ IU/ml and −3.2 log₁₀ IU/ml in TN receiving 200 mg q8 h and 200 mg q12 h, respectively. End of treatment viral decline in these two cohorts was within 0.1 log₁₀ IU/ml of the viral load nadir. HCV RNA reduction in NR was more modest than that observed in upper dose TN cohorts. The overall incidence of viral rebound was low (10/37) and was associated with the R155K substitution in NS3 regardless of the HCV subtype.

Conclusions

Danoprevir was safe and well tolerated when administered for 14 days in patients with chronic HCV genotype 1 infection. Treatment resulted in sustained, multi-log₁₀ IU/ml reductions in HCV RNA in upper dose cohorts. These results support further clinical evaluation of danoprevir in patients with chronic HCV.