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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 2014 Aug 21;78(3):533–542. 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

Ya-Chi Chen 1,✉, Coen Bernaards 2, Rohit Kulkarni 2,*, Sebastian Moreira 1,†, Yonghong Zhu 2,*, Anna Chan 1, Ethan Badman 1, Andrew Ackrill 3, James Thommes 2, Patrick F Smith 1,‡
PMCID: PMC4243904  PMID: 24602156

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

What is Already Known about this Subject —

  • Mericitabine is an orally administered prodrug of a cytidine nucleoside analogue (RO4995855) that is a selective inhibitor of hepatitis C virus (HCV) replication.

What this Study Adds —

  • Early viral kinetics of patients receiving mericitabine-based triple therapy is influenced by mericitabine dose, IL28B genotype and bodyweight, but not by cirrhotic status or HCV genotype 1 subtype.

  • Mericitabine-containing triple therapy minimizes the impact of IL28B on early viral clearance.

  • There is no evidence of a drug–drug interaction between mericitabine and ribavirin.

Introduction

The treatment landscape for chronic hepatitis C is evolving rapidly. The hepatitis C virus (HCV) NS3-4A protease inhibitors boceprevir and telaprevir are the first direct-acting antiviral agents to be approved for this condition. When these drugs are used in combination with peginterferon alfa plus ribavirin they produce superior rates of virological response in HCV genotype 1-infected patients when compared with dual peginterferon alfa plus ribavirin 1–4. However, these first-generation protease inhibitors have several limitations, such as a narrow spectrum of activity (approved for treatment of HCV genotype 1 only), rapid selection of resistant mutants if the regimen is not fully suppressive, and poor tolerability 5–7. For these reasons, the continued development of other classes of direct-acting antiviral agents is essential.

Mericitabine (RG7128; RO5024048) is a di-isobutyl ester prodrug of the cytidine nucleoside analogue RO4995855. After oral administration, mericitabine is rapidly absorbed and converted to the major metabolite RO4995855 (β-d-2′-deoxy-2′-fluoro-2′-C-methylcytidine). RO4995855 is then taken up by cells and phosphorylated to form two active antiviral compounds (RO4995855-TP and RO5012433-TP) that are potent and selective inhibitors of the hepatitis C virus NS5B RNA-dependent RNA polymerase 8–11. Given that the bases of the two active triphosphate metabolites are structurally different (cytidine and uridine, respectively), it could be suggested that mericitabine provides a novel mechanism for delivering a combination therapy. In addition, mericitabine has a high barrier to resistance and pangenotypic antiviral activity, which make it an attractive component in direct-acting antiviral agent combination regimens 12,13.

The major route of elimination for RO4995855 is renal excretion. Approximately 90% of an administered mericitabine dose is excreted in the urine, primarily as RO4995855 11. The mean terminal elimination half-life of RO4995855 ranges from 4.0 to 6.9 h 14.

Virological response to dual peginterferon alfa plus ribavirin therapy is influenced by many patient- and virus-related factors 15. Host IL28B (rs12979860) genotype is the most important baseline predictor of virological response in patients treated with peginterferon plus ribavirin 16. Data are limited on the influence of host IL28B genotype on early viral kinetics during treatment with a triple combination regimen comprised of a direct-acting antiviral agent plus peginterferon alfa and ribavirin. However, it appears that patients with an IL28B CC genotype have higher on- and off-treatment virological response rates than those with a non-CC genotype when treated with an approved protease inhibitor in combination with peginterferon alfa plurs ribavirin 17–19.

In addition, patients infected with HCV genotypes 1 and 4 tend to have lower virological response rates than patients infected with other HCV genotypes when treated with peginterferon alfa plus ribavirin 15. The first-generation HCV protease inhibitors (boceprevir and telaprevir) are approved for use in patients with HCV genotype 1 infection but have shown differences in virological response rates between patients infected with HCV genotypes 1a and 1b treated with these drugs in combination with peginterferon alfa plus ribavirin 2,20,21. This difference appears to be related to the fact that just one nucleotide change is required to generate a resistance-associated variant at position 155 in genotype 1a HCV, whereas two nucleotide changes are required to generate the same resistant mutant in genotype 1b HCV 22.

Patients with advanced fibrosis have lower virological response rates than patients with minimal fibrosis 23, and this has also been reported among patients receiving protease inhibitor-based triple therapy 24,25.

The response to antiviral therapy in HCV-infected patients is heterogeneous. Achievement of a rapid virological response (RVR) at week 4 and complete early virological response (cEVR) at week 12 are associated with sustained virological response to therapy 15. These on-treatment responses can provide critical information to guide drug development, such as dose selection 26.

The efficacy results of two large randomized, placebo-controlled phase 2 trials (PROPEL and JUMP-C) of different dosage regimens of mericitabine plus peginterferon alfa and ribavirin have been published elsewhere 27,28. In this subanalysis of data from these two clinical trials, we carried out a retrospective examination of factors that influence the first-phase (α) slope of viral decline and early on-treatment virological responses (RVR and cEVR) in treatment-naive patients with chronic hepatitis C. In addition, potential pharmacokinetic and pharmacodynamic drug–drug interactions between mericitabine and ribavirin were evaluated.

Methods

Study design

Data included in this analysis were from patients enrolled in the phase 2 PROPEL and JUMP-C studies, in which mericitabine was administered in combination with peginterferon alfa-2a (40KD) plus ribavirin (clinicaltrials.gov NCT00869661 and NCT01057667, respectively) 27,28.

Both studies recruited treatment-naive patients with HCV genotype 1 or 4 infection. In the PROPEL study, patients were randomized to receive either mericitabine at a dosage of 500 or 1000 mg twice daily (bid) or placebo bid for up to 12 weeks in combination with peginterferon alfa-2a (40KD) and ribavirin (Figure 1A). In the JUMP-C study, patients were randomized to receive either mericitabine 1000 mg bid or placebo bid for 24 weeks in combination with peginterferon alfa-2a (40KD) and ribavirin (Figure 1B). The dose of peginterferon alfa-2a (40KD) was 180 μg once weekly in all patients, while the dosage of ribavirin was 1000 mg day−1 for those patients with a bodyweight <75 kg and 1200 mg day−1 for those with a bodyweight ≥75 kg. Treatment was terminated after a total duration of 24 or 48 weeks in both trials depending on treatment assignment and virological response. Individuals who received treatment after 8 or 12 weeks in PROPEL or after week 24 in JUMP-C continued therapy with peginterferon alfa-2a (40KD) and ribavirin.

Figure 1.

Figure 1

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Study design of PROPEL (A) and JUMP-C (B). The rapid virological response (RVR) was defined as undetectable (<15 IU ml−1; limit of detection) hepatitis C virus (HCV) RNA after week 4 of treatment. Abbreviations: MCB, mericitabine; P/R, peginterferon alfa-2a (40KD) 180 μg week−1 plus ribavirin 1000 mg day−1 (<75 kg) or 1200 mg day −1 (≥75 kg)

All individuals included in this analysis had their IL28B genotype assessed at baseline.

Host IL28B genotype analysis

Genetic testing was optional for patients included in the PROPEL and JUMP-C studies. Patients who consented to the genetic sampling protocol provided a 6 ml whole blood sample for the Roche Clinical Repository. The IL28B rs12979860 genotype was determined by Real-Time TaqMan® PCR. Results were reported as CC and non-CC (CT and TT combined).

Viral kinetic analysis

Patients included in the viral kinetic analysis were those who had been randomized to treatment arms A, C, D and E of the PROPEL study and both arms (A and B) of the JUMP-C study (Figure 1A,B). Serum HCV RNA levels were determined by COBAS® AmpliPrep/COBAS® TaqMan HCV Test, with a lower limit of quantification of 43 IU ml−1 and a limit of detection (LOD) of 15 IU ml−1. Assays were performed by Cenetron Diagnostics (Austin, TX, USA). For viral kinetic analysis, the α slope is usually defined as the slope of the HCV RNA concentration–time during the first 3 or 4 days of therapy; however, in both PROPEL and JUMP-C the first postbaseline HCV RNA assessment was scheduled for week 1. For this reason, the α slope here was empirically defined as the rate of decrease in HCV RNA from baseline to week 1. Rapid virological response was defined as undetectable HCV RNA (<15 IU ml−1; LOD) at treatment week 4, and complete early virological response as undetectable HCV RNA (<15 IU ml−1; LOD) at treatment week 12.

Pharmacokinetic analysis

Sparse and intensive pharmacokinetic sampling was performed at designated visits to obtain samples for determination of plasma concentrations of RO4995855 (parent drug of mericitabine) and ribavirin. In the PROPEL study, plasma samples for the sparse pharmacokinetic analysis were collected from 90% (290 of 324) of patients in mericitabine-containing arms at weeks 4 and 12 and in the JUMP-C study from 89% (72 of 81) of patients in the mericitabine-containing arm at weeks 12 and 24. Plasma samples for the intensive pharmacokinetic analysis were collected from patients in mericitabine-containing arms at 0.5 h predose and at 0.5, 1, 2, 3, 4, 6–8 and 12 h postdose (prior to the evening dose of mericitabine and ribavirin) at week 4 in PROPEL (n = 56) and at week 12 in JUMP-C (n = 17).

Plasma concentrations of RO4995855 and ribavirin were determined by a validated liquid chromatography–tandem mass spectrometry method (PharmaNet USA Inc., Princeton, NJ, USA). The lower limit of quantification for RO4995855 was 10.0 ng ml−1 and for ribavirin 20.0 ng ml−1. Assay performance (precision and accuracy) was determined from the analysis of quality control samples. For RO4995855, precision (coefficient of variation) was between 5.37 and 8.00% and between 4.17 and 13.1%, for PROPEL and JUMP-C, respectively. Accuracy (percentage bias) was between −0.667 and 4.27% and between −2.00 and 2.00%, for PROPEL and JUMP-C, respectively. For ribavirin, precision (coefficient of variation) was between 3.51 and 9.17% and between 4.73 and 7.16%, for PROPEL and JUMP-C, respectively. Accuracy (percentage bias) was between −1.50 and −0.250% and between −5.00 and −3.25%, for PROPEL and JUMP-C, respectively.

Pharmacokinetic parameters were calculated by noncompartmental methods using WinNonlin (Professional version 5.2.1; Pharsight Corporation, Mountain View, CA, USA), including area under the plasma concentration–time curve from 0 to the end of the dosing interval (AUCτ), maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax) and minimum observed plasma concentration measured 12 h postdose (Cmin). Steady state was estimated based on the five terminal elimination half-lives of mericitabine (t1/2 ∼4 to 6.9 h) 14,29.

Statistical analyses

Multiple logistic regression analysis was used to explore associations between baseline patient- and disease-related variables and the first (α) phase slope of the decline in serum HCV RNA levels after the start of mericitabine treatment. Variables included in the analysis included the following: patient age (≤50 or >50 years); weight (≤85 or >85 kg); extent of hepatic fibrosis (no cirrhosis or cirrhosis); host IL28B genotype (CC or non-CC); HCV genotype (1a, 1b or 4); and mericitabine dose (500 or 1000 mg). Only patients with complete data sets were included in the analysis. In addition, ANCOVA was performed to test the effect of HCV genotype when other variables were included in the model.

A nonlinear mixed-effects population pharmacokinetic model was used to simulate the Cmin of RO4995855 at week 4 for all patients receiving mericitabine.

Formal statistical testing of differences in the change of HCV RNA between difference dose groups or different IL28B genotype groups were not performed because of the retrospective nature of the analysis, the small number of patients in the various subgroups and the problem with multiple comparisons.

Results

Viral kinetics

Data on IL28B genotype were available for 49 patients who received mericitabine 500 mg bid (CC = 15; non-CC = 34), 153 patients who received mericitabine 1000 mg bid (CC = 42; non-CC = 111) and 108 patients who received placebo (CC = 37; non-CC = 71) in combination with peginterferon alfa-2a (40KD) and ribavirin.

Within a given mericitabine dosage group (500 or 1000 mg bid), steeper α slopes were observed in patients with a CC genotype than with a non-CC genotype, with the steepest slopes in patients with the CC genotype who received mericitabine 1000 mg bid (mean −0.59 log10 HCV RNA day−1; Figure 2). Conversely, the flattest α slope was observed in patients with the non-CC genotype who received mericitabine 500 mg bid (mean −0.28 log10 HCV RNA day−1). The α slope for patients with the CC genotype who received peginterferon alfa-2a (40KD) and ribavirin was less steep than that for patients who received mericitabine in combination with peginterferon alfa-2a (40KD) and ribavirin, while the α slope for patients with the non-CC genotype who received peginterferon alfa-2a (40KD) and ribavirin was essentially flat (mean −0.06 log10 HCV RNA day−1).

Figure 2.

Figure 2

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Comparison of α slopes (reductions in HCV RNA by week 1) by mericitabine dose and host IL28B genotype. Numbers at the top of the figure are the number of patients in each category. Horizontal bar, median; filled circle, mean; boxes show interquartile range; vertical dotted line (whiskers) show maximal and minimal values; open circles show outliers

Mean serum HCV RNA levels decreased during 4 weeks of treatment with mericitabine, but differed by IL28B genotype (Figure 3). Among patients treated with mericitabine 500 mg bid, the mean reductions in HCV RNA were 5.43 and 3.32 log10 IU ml−1 in those with CC and non-CC genotypes, respectively. Among those treated with mericitabine 1000 mg bid, the mean reductions in HCV RNA were 5.42 and 4.47 log10 IU ml−1 for patients with CC and non-CC genotypes, respectively. The mean reduction in HCV RNA levels was numerically similar in patients with CC genotype, irrespective of mericitabine dose; for patients with non-CC genotype, the mean reduction in HCV RNA was numerically higher with mericitabine 1000 mg bid.

Figure 3.

Figure 3

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Mean change in serum HCV RNA level from baseline by dose and host IL28B genotype. Vertical bars represent 95% confidence intervals. Inline graphic, CC, merticitabine 500 mg bid (n = 15); Inline graphic, non-CC, merticitabine 500 mg bid (n = 34); Inline graphic, CC, merticitabine 1000 mg bid (n = 42); Inline graphic, non-CC, merticitabine 1000 mg bid (n = 111); Inline graphic, CC, placebo bid (n = 37); Inline graphic, non-CC, placebo bid (n = 71)

Rapid virological response rates at week 4 and cEVR rates at week 12 are shown in Figure 4 by IL28B genotype and mericitabine dosage. The highest RVR and cEVR rates were observed in patients with a CC genotype. In CC patients, the higher mericitabine dosage (1000 mg bid) was associated with numerically higher RVR rates at week 4 {95.1% [95% confidence interval (CI): 83.9, 98.7%]} than in CC patients who received mericitabine 500 mg bid [64.3% (95% CI: 38.8, 83.7%)] and numerically higher RVR rates than non-CC patients who received mericitabine 1000 mg bid [52.3% (95% CI: 43.0%, 61.3%)] and mericitabine 500 mg bid [26.5% (95% CI: 14.6, 43.1%)]. Among those patients who received a placebo, an RVR was achieved by 33.3% (95% CI: 20.2%, 49.7%) of those with a CC genotype and 5.7% (95% CI: 2.2%, 13.8%) of those with a non-CC genotype. The difference between the two mericitabine dosage groups at week 12 was less marked. Indeed, all patients with a CC genotype who received mericitabine achieved an cEVR at week 12. Among those with a non-CC genotype, 76.5% (95% CI: 60.0%, 87.6%) and 84.6% (95% CI: 76.6%, 90.1%) of those treated with mericitabine 500 and 1000 mg bid, respectively, achieved an cEVR, compared with 28.6% (95% CI: 19.3%, 40.1%) of those who received placebo.

Figure 4.

Figure 4

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Virological response rates at weeks 4 [rapid virological responses (RVR) left] and 12 [complete early virological responses (cEVR) right] according to mericitabine dosage and host IL28B genotype. Vertical lines represent 95% confidence intervals. Inline graphic, mericitabine 500 mg bid plus peginterferon alfa-2a (40KD) and ribavirin; Inline graphic, mericitabine 1000 mg bid plus peginterferon alfa-2a (40KD) and ribavirin; Inline graphic, placebo plus peginterferon alfa-2a (40KD) and ribavirin

Regression analysis

Data from 198 patients who received mericitabine 500 or 1000 mg bid were included in the multiple logistic regression analysis. Four patients with known host IL28B genotype were excluded; two genotype 1 patients because information on subgenotype was missing and two because the reduction in HCV RNA at week 1 of treatment was missing. A summary of the baseline characteristics along with regression coefficients of multiple regression analyses is provided in Table 1. The results indicate that IL28B genotype, bodyweight and mericitabine dose were the strongest predictors of the α slope.

Table 1.

Baseline characteristics of patients with known host IL28B genotype and results of the multiple logistic regression analysis

Variable No. of patients (%) Added slope estimate if variable has this value Estimate (P value)
Host IL28B genotype CC 55 (27.8) CC −0.1920 (<0.0001)
Non-CC 143 (72.2)
Mericitabine dosage 500 mg bid 47 (23.7) 1000 −0.1108 (<0.0001)
1000 mg bid 151 (76.3)
Hepatitis C viral genotype 1a 132 (66.7) 1b 0.0322 (0.1455)
1b 52 (26.3)
4 14 (7.1) 4 0.1192 (0.0017)
Cirrhosis status No 146 (73.7) No −0.0093 (0.6771)
Yes 52 (26.3)
Weight ≤85 kg 126 (63.6) >85 0.0681 (0.0009)
>85 kg 72 (36.4)
Age ≤50 years 106 (53.5) >50 0.0063 (0.7502)
>50 years 92 (46.5)
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To investigate the effect of HCV genotype and subtype (1a, n = 132; 1b, n = 52; and 4, n = 14), ANCOVA was performed on first-phase slope, with all variables in the model being tested against a model without HCV genotype and subtype. The corresponding F-test was F(2,190) = 5.4286, P = 0.0051. When excluding 14 genotype 4 patients from the models, the corresponding F-test was F(1,177) = 1.1553, P = 0.2839. This suggests that the first-phase slopes of patients infected with HCV genotype 1a and 1b are comparable. Due to limited genotype 4 data, the difference between genotype 1a/1b and genotype 4 cannot be established unambiguously.

Pharmacokinetics

Data from intensive pharmacokinetic sampling were available for 14 patients who received mericitabine 500 mg bid, 59 patients who received mericitabine 1000 mg bid, and 35 patients who received placebo bid in the two studies. The characteristics of patients in the three groups were generally similar (Table 2). All 14 of the patients treated with mericitabine 500 mg bid were from PROPEL while for patients treated with mericitabine 1000 mg bid, 42 were from PROPEL and 17 were from JUMP-C. Among patients who received placebo, 13 were from PROPEL and 22 were from JUMP-C. All patients were receiving peginterferon alfa-2a (40KD) and ribavirin.

Table 2.

Baseline characteristics of patients included in the pharmacokinetic analysis

Treatment
Characteristic Mericitabine 500 mg (n = 14) Mericitabine 1000 mg (n = 59) Mericitabine placebo (n = 35)
Male gender [n (%)] 7 (50.0) 40 (67.8) 24 (68.6)
Mean age [years (range)] 48 (24–59) 47 (19–62) 47 (20–65)
Mean weight [kg (range)] 80.9 (51.0–110.7) 81.2 (53.2–108.4) 82.2 (53.0–129.7)
Mean body mass index [kg m−2 (range)] 27.4 (18.7–34.2) 27.0 (20.1–36.1) 26.8 (18.7–35.1)
Mean creatinine clearance [ml min−1 (range)] 128 (74–205) 120 (69–216) 122 (64–266)
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Pharmacokinetic parameters at steady state in patients who underwent intensive pharmacokinetic sampling are summarized in Table 3. In patients treated with mericitabine 1000 and 500 mg bid, the mean steady-state Cmin was 2.01 and 1.24 μg ml−1, respectively (Table 3). In phase 1 studies, the antiviral activity of mericitabine was highly correlated with Cmin (unpublished data on file; Roche, Nutley, NJ, USA).

Table 3.

Summary of steady-state pharmacokinetics of mericitabine and ribavirin

Treatment
Pharmacokinetic parameter Mericitabine 500 mg (n = 14) Mericitabine 1000 mg (n = 59) Mericitabine placebo (n = 35)
Mericitabine
 Mean Cmax ± SD (μg ml−1) 5.70 ± 1.36 9.26 ± 1.85 NA
 Mean AUCτ ± SD (μg h ml−1) 37.0 ± 8.51a 60.3 ± 10.5b NA
 Median Tmax [h (range)] 2.0 (1.0–4.0) 2.0 (0.5–6.5) NA
 Mean Cmin ± SD (μg ml−1) 1.24 ± 0.496a 2.01 ± 0.79b NA
Ribavirin
 Mean Cmax ± SD (μg ml−1) 3.53 ± 1.33 2.96 ± 0.79 3.27 ± 0.98
 Mean AUCτ ± SD (μg h ml−1) 32.60 ± 11.70c 28.50 ± 6.99d 30.00 ± 7.39f
 Median Tmax [h (range)] 2.0 (0.5–4.0) 2.2 (0.5–6.0) 2.0 (0.5–6.2)
 Mean Cmin ± SD (μg ml−1) 2.35 ± 0.80c 2.05 ± 0.53e 2.20 ± 0.56g
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Abbreviations are as follows: AUCτ, area under the plasma concentration–time curve from 0 to the end of the dosing interval; Cmax, maximum observed plasma concentration; Cmin, minimum observed plasma concentration (measured 12 h postdose); NA, not applicable; Tmax, time to reach Cmax.

a

n = 13;

b

n = 57;

c

n = 13;

d

n = 53;

e

n = 56;

f

n = 29;

g

n = 30.

The mean plasma concentration–time profile for RO4995855 in patients who received mericitabine 1000 mg bid in combination with peginterferon alfa-2a (40KD) and ribavirin (n = 59) was numerically similar to that in a group of 10 healthy subjects (50% male, mean age 59 years and mean body mass index 28 kg m−2) who received mericitabine 1000 mg bid alone (Figure 5A). Mean plasma concentrations of ribavirin (Figure 5B) and exposure to ribavirin (Table 3) were numerically similar in patients who received the drug in combination with mericitabine 500 mg bid, mericitabine 1000 mg bid and placebo.

Figure 5.

Figure 5

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Mean plasma concentrations of RO4995855 (A) and ribavirin (B) at steady state in patients who received mericitabine in combination with peginterferon alfa-2a (40KD) and ribavirin in two clinical studies. Data for mericitabine 1000 mg bid monotherapy (A) are from healthy volunteers with normal creatinine clearance who received the drug alone for 5 days. Vertical bars represent standard deviations. Inline graphic, mericitabine 1000 mg bid + peginterferon alfa-2a (40KD) and ribavirin (n = 59); Inline graphic, mericitabine 1000 mg bid monotherapy (n = 10); □, placebo bid + peginterferon alfa-2a (40KD) and ribavirin (n = 35)

Mean simulated exposure (Cmin) to RO4995855 at week 4 was comparable among patients with CC and non-CC IL28B genotypes. Among patients treated with mericitabine 500 mg bid, the mean (± SD) Cmin was 1.13 μg ml−1 (± 0.42 μg ml−1, n = 11) in patients with a CC genotype and 1.14 μg ml−1 (± 0.22 μg ml−1, n = 29) in those with a non-CC genotype. In patients treated with mericitabine 1000 mg bid, the mean Cmin was 2.02 μg ml−1 (± 0.50 μg ml−1, n = 33) and 2.14 μg ml−1 (± 0.52 μg ml−1, n = 88) in patients with a CC genotype and non-CC genotype, respectively.

Discussion

Collectively, the results of analyses presented in this report suggest that host IL28B genotype, mericitabine dose and patient bodyweight are key factors driving the virological response in HCV genotype 1 and 4 patients treated with mericitabine in combination with peginterferon alfa-2a (40KD) plus ribavirin. However, HCV genotype (1 vs. 4), genotype 1 subtype (1a vs. 1b) and hepatic cirrhosis (yes vs. no) are not key factors driving the early virological response. Furthermore, we found no evidence of a pharmacokinetic interaction between mericitabine and ribavirin.

Among HCV genotype 1a, 1b and 4 patients receiving triple therapy, the steepest α slope was observed in patients with the CC genotype who received mericitabine 1000 mg bid and the flattest α slope was observed in patients with the non-CC genotype who received mericitabine 500 mg bid. This is reflected in RVR rates, which were highest in patients with a CC genotype who received the higher dose of mericitabine and lowest in non-CC patients who received the lower dose of mericitabine. The impact of the higher dose on α slope and RVR rates was observed consistently in patients with CC and non-CC host IL28B genotypes.

At week 4, virological response rates were ∼40% higher in patients with a CC genotype than a non-CC genotype regardless of the mericitabine dose. However, at week 12 the difference in virological response rates between patients with CC and non-CC genotypes was <25%. Moreover, in patients with a non-CC genotype the difference between the two mericitabine dosage groups decreased between week 4 and 12. At week 4, the difference in virological response rate between patients treated with mericitabine 1000 and 500 mg bid was ∼25% (52.3 vs. 26.5%, respectively) but was <10% at week 12 (84.6 vs. 76.5%, respectively). Virological response rates were considerably lower at week 4 in both CC and non-CC patients who received placebo plus peginterferon alfa-2a (40KD) and ribavirin. At week 12, an cEVR was achieved by 80.6% of patients with a CC genotype but only 28.6% of patients who were treated with placebo plus peginterferon alfa-2a (40KD) and ribavirin. These data suggest that mericitabine increases virological response rates in patients with both CC and non-CC genotypes and largely overcomes the negative impact of a non-CC genotype on virological response at weeks 4 and 12 of treatment with mericitabine plus peginterferon alfa-2a (40KD) and ribavirin.

The multiple regression analysis confirmed that host IL28B genotype, mericitabine dose and bodyweight are significantly associated with the first (α)-phase slope of the decline in serum HCV RNA levels, while HCV genotype (1a or 1b) and cirrhotic status were not important predictors of virological response (α-phase slope) in this analysis. Owing to the low number of patients with HCV genotype 4 infection, the difference between genotype 1 and 4 cannot be established unambiguously.

Limitations of this analysis include the retrospective nature of the analysis and the low number of patients when stratified for the various factors of interest. For example, the number of patients with HCV genotype 4 infection is too small to draw meaningful conclusions regarding this subgroup. The definition of α slope used in this analysis differs from the traditional definition. Typically, more intensive sampling would have been conducted during the first 3 or 4 days of treatment; the longer sampling period (7 days) introduces a greater degree of error in our estimates of the α slope.

Like all other nucleoside analogues, mericitabine and ribavirin exert their pharmacological effects after being taken up by cells and undergoing phosphorylation 30,31. Thus, it is important to know whether the antiviral effects of mericitabine are affected by ribavirin through a drug–drug interaction. Our data showed no alteration in plasma exposure of ribavirin when given with or without mericitabine and, likewise, no alteration in plasma exposure of mericitabine given with or without ribavirin. Although the absence of a drug–drug interaction in plasma does not necessarily preclude there being an intracellular interaction between metabolites of these drugs, an intercellular interaction between metabolites of mericitabine and ribavirin seems unlikely because mericitabine is a cytidine analogue (pyrimidine nucleoside) and ribavirin is a guanosine analogue (purine nucleoside). Different enzymes are involved in the phosphorylation of purine and pyrimidine nucleosides, which is thought to be the rate-limiting step for activation of these drugs. It seems unlikely, therefore, that the intracellular metabolites of either drug would alter the phosphorylation of the other, which is also supported by in vitro data suggesting that there is no intracellular interaction between these two drugs (unpublished data on file; Roche, Nutley, NJ, USA). Furthermore, data from an in vitro study show that these two nucleoside analogues (mericitabine and ribavirin) have additive antiviral effects in the hepatitis C replicon system 32.

In conclusion, our data suggest that combined treatment with mericitabine plus peginterferon alfa-2a (40KD) and ribavirin results in at least additive antiviral activity, with no evidence of a drug–drug interaction between mericitabine and ribavirin. The early viral kinetics, as assessed by the first-phase slope, of patients receiving mericitabine-based triple therapy are influenced by mericitabine dose, host IL28B genotype and bodyweight, but not by cirrhotic status or HCV genotype 1 subtype. Patients treated with the higher dose of mericitabine (1000 mg bid) achieved higher RVR rates across different IL28B genotypes compared with patients who were treated with the lower dose (500 mg bid). The mericitabine-containing triple therapy regimen minimizes the impact of IL28B genotype over time on the early on-treatment virological response compared with peginterferon plus ribavirin dual therapy.

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: Y-CC is an employee of Roche and holds stock options for Roche; CB is an employee of Genentech; RK is a former employee of Genentech; SM is a former employee of Roche; YZ is a former employee of Genentech and holds stock options for Roche; AC is a former employee of Roche; EB is a former employee of Roche and has received royalties from Purdue University for his contribution to a patent for a mass spectrometer; AA is an employee of Roche; JT is an employee of Roche-Genentech; PFS is a former employee of Roche.

This research was funded by F. Hoffmann-La Roche Ltd. Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd.

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