| |
Do Differences in Pegylation of Interferon Alfa Matter?
Commentary by Stefan Zeuzem
|
| |
| |
Gastroenterology Jan 2010
Stefan Zeuzem
Department of Medicine, J.W. Goethe University Hospital, Frankfurt, Germany
Conflicts of interest The author discloses the following: Clinical investigator, consultant and member of speaker's bureau for Human Genome Sciences, Novartis, Roche, and Schering-Plough.
published online 23 November 2009.
See "Randomized study of peginterferon-α2a plus ribavirin vs peginterferon-α2b plus ribavirin in chronic hepatitis C," by Rumi MG, Aghemo A, Prati GM, et al, on page 108; and "Peginterferon alpha-2a plus ribavirin is more effective than peginterferon alpha-2b plus ribavirin for treating chronic hepatitis C virus infection," by Ascione A, De Luca M, Tartaglione MT, et al, on page 116.
Modification of therapeutic molecules through the attachment of polyethylene glycol (PEG) moieties ("pegylation") is a common approach to optimize delivery of parenteral agents. Pegylation of therapeutic proteins modifies immunologic, pharmacokinetic, and in turn, their pharmacodynamic properties.1 Pegylation technology has been applied to improve the pharmacokinetics and pharmacodynamics of interferon alfa, to avoid large fluctuating serum concentrations and the inconvenient dosing regimens associated with conventional interferon alfa. Two PEG-modified interferons have been approved for the treatment of chronic hepatitis C (HCV; peginterferon alfa-2a and alfa-2b). The size, geometry, and attachment site of the PEG moiety are relevant for subsequent pharmacokinetic properties of interferon alfa.1
Peginterferon alfa-2a is monopegylated with a 40-kDa branched PEG moiety and consists of 4 major positional isomers involving Lys31, Lys121, Lys131, and Lys134 of interferon alfa-2a. Peginterferon alfa-2 is absorbed at a sustained rate, the absolute bioavailability is at least 60%. After a single dose of 180 µg in healthy volunteers the mean maximum serum concentration (Cmax) was 14.2 µg/L and was reached in a mean time (Tmax) of 78 hours.2 After multiple doses of peginterferon alfa-2a (180 µg weekly) in patients with chronic HCV, Cmax and Tmax values were 25.6 µg/L and 45 hours, respectively.2 At steady state, which is attained 5-8 weeks after initiation of therapy, the ratio of serum peak to trough concentrations of peginterferon alfa-2a is about 1.5-2.0, indicating that serum concentrations of the drug are sustained during the 1-week dosage interval. It is anticipated that peginterferon alfa-2a will be undetectable in the serum 4-6 weeks after discontinuation of 48 weeks' treatment (180 µg weekly). Peginterferon alfa-2a displays restricted biodistribution with highest concentrations occurring in the liver. The drug is cleared by both the liver and the kidney.2
Approximately 95% of peginterferon alfa-2b is present as 1 of 14 monopegylated (12-kDa) positional isomers, with pegylation derivatizing amino acids containing nucleophilic side chains, including lysine, serine, tyrosine, histidine, and N-terminal cysteine. About 50% of peginterferon alfa-2b is monopegylated on the His34 residue of the interferon alfa-2b protein. The His34 positional isomer retains a high antiviral specific activity; however, it is also the most susceptible residue for hydrolysis. The absorption half-life for peginterferon alfa-2b is longer than for unmodified interferon alfa. In patients who received 0.35, 0.7, or 1.4 µg/kg peginterferon alfa-2b, mean peak serum concentrations (Cmax) occurred between 20 and 32 hours at week 1 and between 22 and 29 hours at week 4 after dosing, suggesting no changes in absorption rate relative to dose or duration of treatment.2 In patients treated with peginterferon alfa-2b, the variability of time-drug concentration profiles after subcutaneous administration is lower compared with those treated with peginterferon alfa-2a. Accumulation of peginterferon alfa-2b based on the ratio of week 1 and week 4 AUC values ranged from 0.9 to 1.2. Mean elimination half-life values at week 1 and week 4 were similar (40-58 hours), suggesting that the elimination of peginterferon alfa-2b was not altered in patients after weekly dosing.2 The volume of distribution for peginterferon alfa-2b is approximately 30% lower than that for conventional interferon alfa (0.99 vs 1.4 l/kg). Because of the wide distribution of both unmodified and the linear 12-kDa peginterferon alfa-2b throughout body fluids and tissues, their Vd is dependent on the individual's body weight and weight-based dosing is thus recommended. Clearance of peginterferon alfa-2b is about one tenth that of unmodified interferon alfa (22 vs 231 mL/h per kilogram). Renal clearance accounts for 30% of peginterferon alfa-2b, with the remainder cleared through hepatic catabolism and degradation after interaction with cellular interferon receptors.2
The initial decline of viremia in patients treated with interferon α is characterized by a convex shape. The first phase (day 1) of the initial decline is rapid and dose dependent, whereas the second phase (≥day 2) of the initial decline is highly variable and shows a much slower decline.3 Oscillations of serum HCV RNA seem to be present in a considerable number of patients treated with standard interferon alfa 3 times per week. In particular, an intermediate increase of viral load after 24 hours was observed in most patients treated with standard interferon alfa.3
HCV RNA levels have been shown also to correlate inversely with drug levels of both pegylated interferons. Owing to greater variations in peak-to-trough ratios for peginterferon alfa-2b than peginterferon alfa-2a, HCV RNA levels tend to fluctuate more (at least within the initial 4 weeks of therapy) in patients treated with peginterferon alfa-2b than in those treated with peginterferon alfa-2a.2 The increase of HCV RNA at the end of the peginterferon alfa-2b dosing interval can be reduced by using higher doses4 or twice weekly injections of standard doses.5
Direct pharmacodynamic comparisons of the 2 pegylated interferons for 4-12 weeks showed either a greater mean decline in HCV RNA in patients treated with peginterferon alfa-2b compared with patients treated with peginterferon alfa-2a6 or vice versa,7 or no difference.8 None of these earlier trials reported virologic response rates at the end of therapy or after a 24-week follow-up period. Thus, it remained unknown for some years whether the differences in the pharmacokinetic properties and initial viral decline with the 2 pegylated interferons translate into differences in the primary clinical end point, namely, sustained virologic response.
The largest end point head-to-head trial (IDEAL study) comparing both peginterferons was sponsored by Schering-Plough and randomized >3,000 HCV-1 infected patients into 3 arms: peginterferon alfa-2b 1.0 µg/kg per week, peginterferon alfa-2b 1.5 µg/kg, and peginterferon alfa-2a 180 µg per week, all in combination with ribavirin.9 Ribavirin doses and dose reduction schedules differed according to the respective label. Higher virologic end-of-treatment rates were observed for patients treated with peginterferon alfa-2a compared with those treated with peginterferon alfa-2b. Virologic relapse rates, which had been similar in the pivotal phase 3 trials for both peginterferons (19% and 18%, respectively)10, 11 differed significantly in the IDEAL trial (27.8% vs 19.9%),9 leading to similar sustained virologic response rates in all 3 arms (Table 1). Types and frequencies of adverse events were similar among the different treatment groups.9
In this issue of Gastroenterology, Rumi et al12 report the results of their head-to-head study comparing efficacy and safety of the 2 peginterferons in combination with ribavirin. This investigator-initiated study enrolled 431 treatment-naïve patients infected with HCV genotypes 1, 2, 3, or 4 who were treated with standard doses for 48 and 24 weeks. Ribavirin was dosed according to the respective labels; thus, ribavirin doses for patients treated with peginterferon alfa-2a and -2b differed slightly. However, ribavirin dose reductions in patients developing anemia were the same in both treatment arms (200-mg steps). The intention-to-treat analysis of the study showed similar rates of treatment-related serious adverse events and discontinuation rates for side effects. Peginterferon alfa-2a dosing had to be reduced more frequently than peginterferon alfa-2b to manage neutropenia. Sustained virologic response rates were significantly higher in patients treated with peginterferon alfa-2a compared with alfa-2b (Table 1).12
Similar results are reported in the study by Ascione et al,13 also published in this issue of Gastroenterology. In this investigator-initiated study, which enrolled 320 treatment-naïve patients infected with HCV genotypes 1, 2, 3, or 4, ribavirin dosing was identical for patients randomized to receive peginterferon alfa-2a or alfa-2b. Sustained virologic response rates were significantly greater in patients treated with peginterferon alfa-2a compared with those treated with peginterferon alfa-2b (Table 1), whereas type and incidence of adverse events was very similar between the 2 groups.13
Higher sustained virologic response rates of peginterferon alfa-2a over peginterferon alfa-2b have also been reported in a large retrospective study at the Veteran Hospitals in the United States.14 A recent Cochrane systematic review of randomized clinical trials comparing both peginterferons identified 13 randomized studies including 5124 patients. The meta-analysis of sustained virologic response included 8 trials and 4293 patients, and yielded an estimated effect in favor of peginterferon alfa-2a (relative risk [RR], 1.10; 95% confidence interval [CI], 1.03-1.18; P = .004). Subgroup analyses on genotype and treatment history yielded similar results for all subgroups. The meta-analysis of severe adverse events included 11 trials and revealed no significant differences between peginterferon alfa-2a and alfa-2b (RR, 0.80; 95% CI, 0.51-1.26; P = .35).15
Taken together, since the publication of the pivotal phase 3 trials for peginterferon alfa-2a and alfa-2b in combination with ribavirin,10, 11 it took another 8 years to characterize the pharmacodynamic differences between the 2 drugs in detail. At the dawn of new direct antiviral drugs against the HCV16 we need now to investigate how important the observed differences between the peginterferons (and other long-acting interferons such as albumin interferon) are in combination with HCV NS3/4A protease and NS5B polymerase inhibitors.
|
|
| |
| |
|
|
|
