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Br J Clin Pharmacol. 2014 Sep;78(3):533-42. doi: 10.1111/bcp.12369.

Understanding the effect of the HCV polymerase inhibitor mericitabine on early viral kinetics in the phase 2 JUMP-C and PROPEL studies.

Author information

1
Hoffmann-La Roche Inc., Nutley, NJ, USA.

Abstract

AIMS:

The aim was to evaluate early viral kinetics in patients receiving mericitabine [hepatitis C virus (HCV) nucleoside polymerase inhibitor] with peginterferon alfa-2a (40KD) and ribavirin in two clinical trials (PROPEL and JUMP-C).

METHODS:

We examined rapid virological responses (RVRs; week 4 HCV RNA <15 IU ml(-1) ) and complete early virological responses (cEVR; week 12 HCV RNA <15 IU ml(-1) ) in HCV genotype 1/4-infected patients receiving mericitabine (500 or 1000 mg) or placebo twice daily plus peginterferon alfa-2a and ribavirin.

RESULTS:

Among IL28B rs12979860 CC genotype patients receiving 500 or 1000 mg mericitabine or placebo, respectively, RVR rates were 64.3% (95% confidence interval: 38.8-83.7%), 95.1% (83.9-98.7%) and 33.3% (20.2-49.7%), and cEVR rates were 100% (78.5-100%), 100% (91.4-100%) and 80.6% (65.0-90.3%). Among non-CC genotype patients, RVR rates were 26.5% (14.6-43.1%), 52.3% (43.0-61.3%) and 5.7% (2.2-13.8%), and cEVR rates were 76.5% (60.0-87.6%), 84.6% (76.6-90.1%) and 28.6% (19.3-40.1%), respectively. In multiple regression analysis, IL28B genotype (P < 0.0001), mericitabine dose (P < 0.0001) and bodyweight (P = 0.0009) were associated with first-phase (α) slope (change in log10 HCV RNA from baseline to week 1).

CONCLUSIONS:

Mericitabine-containing triple therapy reduces the impact of IL28B genotype on RVR and cEVR compared with peginterferon alfa-2a and ribavirin dual therapy. The IL28B genotype, mericitabine dose and bodyweight are the most important factors associated with the α slope, and there is no evidence of a pharmacokinetic drug-drug interaction between mericitabine and ribavirin.

KEYWORDS:

hepatitis C virus polymerase inhibitor; mericitabine; pharmacodynamics; pharmacokinetics; ribavirin

PMID:
24602156
PMCID:
PMC4243904
DOI:
10.1111/bcp.12369
[Indexed for MEDLINE]
Free PMC Article

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