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Antiviral activity, safety, and pharmacokinetics of danoprevir/ritonavir plus PEG-IFN α-2a/RBV in hepatitis C patients - pdf attached
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Articles in Press
Journal of Hepatology April 2011
Edward J. Ganea, Regine Rouzierb, Catherine Stedmanc, Alicja Wiercinska-Drapalod, Andrzej Horbane, Linda Changf, Ying Zhangf, Pratibha Sampeurf, Isabel Najeraf, Patrick Smithf, Nancy S. Shulmanf, Jonathan Q. Tran
Received 20 October 2010; received in revised form 22 December 2010; accepted 30 January 2011. published online 25 February 2011.
Accepted Manuscript
"In conclusion, this study confirms that the use of low dose danoprevir plus low dose ritonavir to reduce the overall danoprevir exposure is a feasible therapeutic strategy and, in particular, that danoprevir/r regimens are safe and well tolerated, when administered together with peginterferon alfa-2a (40KD) plus ribavirin for 14 days. Danoprevir/r regimens show potent viral suppression with no evidence of danoprevir resistance up to 15 days of administration in treatment-naive patients. Furthermore, reduction of danoprevir exposure by using a combination of low dose danoprevir and low dose ritonavir is expected to significantly reduce the probability of ALT elevations. The excellent antiviral activity and tolerability of all danoprevir/r regimens in this study support ongoing and future clinical trials of danoprevir/r in patients with genotype 1 HCV infection."
"All 8 patients (100%) treated with the highest dose of danoprevir/r (200/100 mg BID) had undetectable HCV RNA levels (<15 IU/mL) on day 15.....Viral breakthrough; partial response or non-response was not observed in any patient during treatment with danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin (Figure 1); thus, resistance analysis was performed through population sequencing of baseline samples for all patients, with no danoprevir resistance mutations observed in any patient...... Doubling the dose of danoprevir (100/100 mg BID to 200/100 mg BID) resulted in an approximately 4- to 5-fold increase in exposure...... The rate and magnitude of reduction in serum HCV RNA levels with all danoprevir/r regimens plus peginterferon alfa-2a (40KD)/ribavirin in the present study appeared to be at least comparable with a telaprevir-based triple therapy regimen in the same dosing duration [13]. On day 15 of telaprevir plus peginterferon alfa-2a/ribavirin treatment, 3 of 12 (25%) patients had undetectable HCV RNA (<10 IU/mL, Roche Taqman Assay). Whereas in the present study 6 of 9 (67%) patients treated with danoprevir/r 100/100 mg BID plus peginterferon alfa-2a/ribavirin had undetectable HCV RNA (<15 IU/mL) at the same time-point.....danoprevir/r has a promising safety profile and was generally well tolerated..........Estimated danoprevir Ctrough,ss values in the liver for danoprevir/r 100/100 mg BID, 200/100 mg QD, and 200/100 mg BID are approximately 1.5-fold, 0.7-fold, and 10-fold above the replicon assay EC90 value of 14 nM (10.2 ng/mL)......The use of low dose ritonavir as a pharmacokinetic enhancer is faced with the challenges associated with potential drug-drug interactions."
Abstract
Background and Aims
Danoprevir (RG7227; ITMN-191) is a potent inhibitor of the HCV NS3/4A serine protease. The aims of this double-blind, placebo-controlled, multiple-ascending dose phase Ib study were to evaluate safety, tolerability, antiviral activity, resistance and pharmacokinetics of once- and twice-daily danoprevir in the presence of low-dose ritonavir (danoprevir/r) and in combination with peginterferon alfa-2a (40KD)/ribavirin in treatment-naive HCV genotype 1 patients.
Methods
Thirty eligible patients were enrolled into 3 cohorts and treated with danoprevir/r or placebo/r all in combination with peginterferon alfa-2a (40KD)/ribavirin for 15 days. Cohort 1 received danoprevir/r at 100/100mg twice daily; Cohort 2 200/100mg once daily; and Cohort 3 200/100mg twice daily.
Results
The median reductions in HCV RNA from baseline after 14 days of treatment (day 15) were -5.1, -4.8 and -4.6 log10 IU/mL in Cohorts 1, 2 and 3, respectively, and -2.7 log10 in placebo/r and peginterferon alfa-2a (40KD)/ribavirin recipients. Viral breakthrough was not observed in any patient. On day 15 HCV RNA was undetectable (<15 IU/mL) in 6/9 (67%), 4/8 (50%) and 8/8 (100%) patients in Cohorts 1, 2 and 3 respectively. When co-administered with low dose ritonavir, danoprevir concentrations reached steady state between 6 to 10 days of dosing. Danoprevir exposures increased more than dose proportionally between 100/100 mg and 200/100 mg. Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin was well-tolerated with no safety-related discontinuations.
Conclusions
Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin provides profound and robust reductions in serum HCV RNA, at substantially lower systemic exposures compared to those observed with higher doses of danoprevir in the absence of ritonavir. These results support further studies of danoprevir/r.
Introduction
Approximately half of patients infected with genotype 1 hepatitis C virus (HCV) achieve a sustained virological response (SVR) after treatment with the combination of pegylated interferon plus ribavirin for 48 weeks, the current standard of care for chronic HCV infection [1]. Thus, new drugs are required to improve treatment efficacy.
Several classes of direct acting antiviral agents are under clinical development with the primary objective of increasing SVR rates in genotype 1 HCV infection. Danoprevir (RG7227; ITMN-191) is a potent, selective, macrocyclic inhibitor of the HCV NS3/4A serine protease [2,3]. When administered orally to patients with chronic hepatitis C at doses up to 900 mg twice daily in combination with peginterferon alfa-2a (40KD) plus ribavirin for 15 days, the median reduction in serum HCV RNA level was 5.3 log10 and no patient experienced viral breakthrough [4]. Treatment of patients with the 900 mg twice daily dose in an ongoing phase IIb study has been discontinued because of asymptomatic AIDS Clinical Trials Group (ACTG) Grade 4 alanine aminotransferase (ALT) elevations (>10 times above the upper limit of normal) documented in three out of 194 patients [5]. Higher danoprevir systemic exposure (area under the plasma concentration versus time curve [AUC] and observed maximum plasma concentration [Cmax]) was subsequently shown to be associated with higher probability of ALT elevations [6].
Ritonavir, an HIV-1 protease inhibitor (PI), is currently used as a pharmacokinetic enhancer at low doses ranging from 100 to 400 mg/day in combination with other HIV PIs [7]. Although ritonavir displays a mixed inhibition and induction effect on the cytochrome P450 3A (CYP3A), its inhibitory effect is predominant at steady state [8] As a result, when co-administered with a low sub-therapeutic dose of ritonavir, the pharmacokinetics of HIV PIs that are substrates of CYP3A are significantly enhanced, allowing for simplification of the dosing regimen of most HIV PIs, including a reduction in the dosing frequency and/or a decrease in the number of tablets or capsules needed to maintain therapeutic drug concentrations [7].
Since danoprevir is a substrate of CYP3A, low-dose ritonavir also has the potential to enhance the pharmacokinetic profile of danoprevir. Such changes have been demonstrated in healthy volunteers who received danoprevir 100 mg single dose before and after administration of ritonavir 100 mg twice daily for 10 days. Danoprevir area under the curve from time 0 to infinity (AUC0-°), Cmax, and plasma concentration 12 hours after dosing (C12h) were increased by approximately 5-fold, 3-fold, and 42-fold, respectively, compared with danoprevir alone [9]. Given the substantial effect of low-dose ritonavir on danoprevir C12h, which is equivalent to trough concentration (Ctrough) for a twice-daily regimen, a reduced danoprevir dose and overall exposure (AUC and Cmax) could be explored while still maintaining danoprevir concentrations above the efficacy threshold.
The objectives of this trial were to evaluate the safety, tolerability, antiviral activity, and pharmacokinetics of once- and twice-daily reduced danoprevir doses in the presence of low-dose ritonavir (danoprevir/r) and in combination with peginterferon alfa-2a (40KD) plus ribavirin in patients with chronic hepatitis C genotype 1 infection.
Results
A total of 30 patients were treated in this study and divided into 3 cohorts. 25 patients were assigned to 1 of the 3 danoprevir/r dosing cohorts, and 5 were assigned to placebo/r. Baseline characteristics are described in Table 1.
HCV RNA levels
Individual HCV RNA levels during the 2-week treatment of danoprevir/r or placebo/r plus peginterferon alfa-2a (40KD)/ribavirin are shown in Figure 1. The earliest timepoint for undetectable HCV RNA was observed at day 3 in each dose level. Between 63% and 67% of patients treated with twice-daily danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin had undetectable HCV RNA (<15 IU/mL) by day 9 of treatment. All 8 patients (100%) treated with the highest dose of danoprevir/r (200/100 mg BID) had undetectable HCV RNA levels (<15 IU/mL) on day 15, as compared with 6 of 9 (67%) patients treated with the lower BID regimen (100/100 mg) and 4 of 8 (50%) of those treated with the QD regimen (200/100 mg) (Figures 3 and 4, Table 2).
HCV RNA levels decreased by -4.6 to -5.1 log10 IU/mL between baseline and day 15 in the 3 danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin cohorts, compared to only a -2.7 log10 IU/mL reduction in the cohort treated with peginterferon alfa-2a (40KD)/ribavirin in combination with placebo/r (Figures 1 and 2, Table 2).
All patients experienced a continuous viral load decline. Viral breakthrough; partial response or non-response was not observed in any patient during treatment with danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin (Figure 1); thus, resistance analysis was performed through population sequencing of baseline samples for all patients, with no danoprevir resistance mutations observed in any patient. No further analysis of on-treatment samples was performed.
Pharmacokinetics
Following oral administration of danoprevir/r with food, danoprevir median Tmax ranged between 2.0 and 3.0 hours. In the presence of low-dose ritonavir, danoprevir concentrations increased during the first 2 to 3 days of dosing and then gradually declined toward steady state after 6 to 10 days of dosing (data not shown), reflecting the mixed inhibition/induction effect of ritonavir on CYP3A. Danoprevir steady-state pharmacokinetic parameters are summarized in Table 3. Danoprevir exposures increased more than dose proportionally between 100/100 mg and 200/100 mg. Doubling the dose of danoprevir (100/100 mg BID to 200/100 mg BID) resulted in an approximately 4- to 5-fold increase in exposure. The terminal elimination phase of the plasma concentration-time profiles was not adequately characterized and therefore terminal elimination half life (t1/2) cannot be appropriately determined.
Exposure-response relationships were evaluated by fitting Emax-type models via non-linear regression. No significant relationship between danoprevir exposure parameters and various measures of antiviral activity were identified (data not shown).
Safety
Safety and tolerability data are presented in Table 4. There were no treatment- related discontinuations, withdrawals, or dose reductions of danoprevir/r. Only one serious adverse event was reported during the study. This patient had been assigned to the danoprevir/r 100/100 mg BID and experienced altered mood during the follow-up period 2 wks after the last dose of danoprevir/r while receiving ongoing treatment with peginterferon alfa-2a (40 KD) plus ribavirin. The patient required overnight hospitalization.
Mean serum ALT values decreased during treatment in all treatment groups. No patient in any of the 3 danoprevir/r cohorts experienced Grade 3 or 4 ALT elevations.
Adverse events were generally mild in severity and similar in nature to those associated with treatment with peginterferon alfa-2a (40KD) plus ribavirin.
Discussion
This study demonstrates that danoprevir/r in combination with SOC provides significant reductions in serum HCV RNA levels at much lower overall exposures (AUC and Cmax) than with danoprevir alone. Danoprevir/r in combination with peginterferon alfa-2a (40 KD) plus ribavirin has a promising safety profile and was well tolerated in patients infected with genotype 1 HCV.
Danoprevir/r regimens provided potent antiviral activity. Indeed, in each of the 3 danoprevir/r cohorts, a higher proportion of patients had undetectable HCV RNA levels after 14 days of treatment (50-100%) than in a historical control group treated with danoprevir 900 mg BID (14%) [4]. Similarly, the time taken to achieve undetectable HCV RNA for all three danoprevir/r cohorts in this study (day 9 for BID regimens and day 12 for QD regimen) appears to be faster than in the historical 900 mg BID group (day 15) [4]. It should be noted that the comparison to historical 900 mg BID data is limited by two major factors: 1) a small sample size and 2) the different lower limit of detection for the HCV RNA assay (9.3 IU/mL for historical vs 15 IU/mL for this study).
The addition of an investigational HCV protease inhibitor (telaprevir) to peginterferon alfa-2a (40KD)/ribavirin significantly increased both the early on-
treatment virological response rate at week 4 (90% vs. 15% with peginterferon alfa-2a (40KD)/ribavirin alone) and the SVR rate (75% vs. 45% with peginterferon alfa-2a (40KD)/ribavirin alone) in genotype 1 patients enrolled in phase II clinical trials [10-12]. The rate and magnitude of reduction in serum HCV RNA levels with all danoprevir/r regimens plus peginterferon alfa-2a (40KD)/ribavirin in the present study appeared to be at least comparable with a telaprevir-based triple therapy regimen in the same dosing duration [13]. On day 15 of telaprevir plus peginterferon alfa-2a/ribavirin treatment, 3 of 12 (25%) patients had undetectable HCV RNA (<10 IU/mL, Roche Taqman Assay). Whereas in the present study 6 of 9 (67%) patients treated with danoprevir/r 100/100 mg BID plus peginterferon alfa-2a/ribavirin had undetectable HCV RNA (<15 IU/mL) at the same time-point. The addition of an HCV protease inhibitor to standard therapy can potentially provide a much more effective therapeutic regimen for patients with genotype 1 infection.
Although low dose ritonavir is commonly used as a pharmacokinetic enhancer for HIV protease inhibitors, this pharmacological strategy to optimize pharmacokinetics of HCV protease inhibitors that are CYP3A substrates has only been recently explored. Following 2-week treatment of narlaprevir/r 400/200 mg BID plus Peg-IFN alfa-2b in eight treatment-naive patients, four patients (50%) had HCV RNA < 25 IU/mL [14]. In comparison, 2-week treatment of danoprevir/r 100/100 mg BID and 200/100 mg BID plus peginterferon alpha-2a/ribavirin resulted in 67% (6/9) and 100% (8/8) of patients with undetectable HCV RNA (< 15 IU/mL).
Naturally occurring resistant mutations to HCV protease inhibitors may be present in a small number of treatment-naive individuals with genotype 1 HCV infection[15] and after the initiation of protease inhibitor monotherapy, viral breakthrough occurred within 1 to 2 weeks [16,17]. The emergence of protease- inhibitor resistant variants correlating to viral breakthrough has also been described in patients receiving the combination of a protease inhibitor plus peginterferon alfa-2a (40KD)/ribavirin [10,11]. However, in the present study, viral breakthrough was not observed in any patient during treatment with danoprevir/r in combination with peginterferon alfa-2a (40KD)/ribavirin.
Certain adverse events have been observed during therapy with HCV investigational protease inhibitors (for example rash with telaprevir [10-12]; anemia with boceprevir [18]). Notably, severe cardiotoxicity resulted in the discontinuation of ciluprevir, the first drug in the class to be studied in humans [19]. When administered for 15 days in combination with peginterferon alfa-2a (40KD)/ribavirin in 25 patients, danoprevir/r has a promising safety profile and was generally well tolerated. There was no evidence of cardiotoxicity or hepatotoxicity, and the incidence of individual adverse events was low.
Danoprevir 900 mg BID regimen in an ongoing phase II study has been discontinued because of asymptomatic Grade 4 ALT elevations. High exposure to danoprevir was associated with Grade 3 and 4 elevations in ALT, whilst no Grade 4 ALT elevations were observed for AUC ² 782 ng„hr/mL [6]. Given that all three danoprevir/r regimens had substantially lower mean AUC values than 782 ng„hr/mL, the probability of ALT elevations in patients treated with danoprevir/r regimens in future clinical studies is expected to be substantially reduced or eliminated.
Liver exposure is considered important for the efficacy of a drug meant to disrupt HCV replication. The liver-to-plasma AUC ratios in monkeys and rats are approximately 10-fold and 127-fold, respectively. [3] The difference in the liver-to- plasma ratios between species could be attributed to differences in plasma protein binding. Based on the plasma protein binding of 99.9% in rats, 92.5% in monkeys, and 97.9% in humans [20] the estimated human liver-to-plasma ratios for danoprevir is approximately 43-fold using simple linear regression. Estimated danoprevir Ctrough,ss values in the liver for danoprevir/r 100/100 mg BID, 200/100 mg QD, and 200/100 mg BID are approximately 1.5-fold, 0.7-fold, and 10-fold above the replicon assay EC90 value of 14 nM (10.2 ng/mL).[3] It should be emphasized that the efficacious Ctrough,ss value for danoprevir has not been established. The lack of exposure-response relationship and the potent antiviral activity associated with all three danoprevir/r regimens suggests that a lower Ctrough,ss may be sufficient. However, additional pharmacokinetics and pharmacodynamics data (e.g., efficacy, resistance) from phase II and/or III studies may help to elucidate the efficacious Ctrough,ss value.
The use of low dose ritonavir as a pharmacokinetic enhancer is faced with the challenges associated with potential drug-drug interactions. Experience in the treatment of HIV shows that drug-drug interactions associated with the use of ritonavir-boosted HIV protease inhibitors are manageable [21]. The available data and knowledge on those interactions would be valuable for use of danoprevir/r in the treatment of HCV.
In conclusion, this study confirms that the use of low dose danoprevir plus low dose ritonavir to reduce the overall danoprevir exposure is a feasible therapeutic strategy and, in particular, that danoprevir/r regimens are safe and well tolerated, when administered together with peginterferon alfa-2a (40KD) plus ribavirin for 14 days. Danoprevir/r regimens show potent viral suppression with no evidence of danoprevir resistance up to 15 days of administration in treatment-naive patients. Furthermore, reduction of danoprevir exposure by using a combination of low dose danoprevir and low dose ritonavir is expected to significantly reduce the probability of ALT elevations. The excellent antiviral activity and tolerability of all danoprevir/r regimens in this study support ongoing and future clinical trials of danoprevir/r in patients with genotype 1 HCV infection.
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