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A Randomised Trial to Compare the Pharmacokinetic, Pharmacodynamic, and Antiviral Effects of Peginterferon Alfa-2B and Peginterf

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A Randomised Trial to Compare the Pharmacokinetic, Pharmacodynamic, and Antiviral Effects of Peginterferon Alfa-2B and Peginterf Journal of Hepatology 45 (2006) 204–213 www.elsevier.com/locate/jhep A randomised trial to compare the pharmacokinetic, pharmacodynamic, and antiviral effects of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C (COMPARE) Marcelo Silva1,*, Jorge Poo2, Frank Wagner3, Mary Jackson4, David Cutler4, Michael Grace4, Ronald Bordens4, Connie Cullen4, Joann Harvey4, Mark Laughlin4 1Hospital Universitario Austral, Pilar, Argentina 2CIF-BIOTEC/Hospital Medical Sur, Mexico City, Mexico 3Clinical Research, Berlin, Germany 4Schering-Plough Research Institute, Kenilworth, NJ, USA See Editorial, pages 172–173 Background/Aims: To compare the pharmacokinetics, pharmacodynamics, and antiviral activity of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C virus genotype 1. Methods: Thirty-six patients were randomised to peginterferon alfa-2b (1.5 lg/kg/week) or peginterferon alfa-2a (180 lg/week) for 4 weeks, then in combination with ribavirin (13 mg/kg/day) for a further 4 weeks. The pharmacokinetic profile of both peginterferons, mRNA expression of a selected group of interferon-induced gene transcripts, and serum HCV-RNA levels were assessed. Results: Patients receiving peginterferon alfa-2b had significantly greater up-regulation of interferon-alfa response genes compared with those receiving peginterferon alfa-2a. Correspondingly, patients treated with peginterferon alfa-2b also had a significantly greater log10 maximum and log10 time-weighted average decrease in serum HCV-RNA. A greater propor- tion of peginterferon alfa-2b patients achieved a P2.0 log10 reduction in serum HCV-RNA levels by week 8 (72% vs 44% of peginterferon alfa-2a patients, P = 0.09). There was an approximately 16-fold greater exposure to peginterferon in the serum of patients treated with peginterferon alfa-2a. Conclusions: These findings suggest that the biological activity, measured by early interferon-induced gene transcripts and early antiviral responsiveness, may have been greater in patients treated with peginterferon alfa-2b despite their lower exposure to the drug compared with patients treated with peginterferon alfa-2a. Ó 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Chronic hepatitis C infection; Pegylated interferon; Peginterferon alfa-2b; Peginterferon alfa-2a; Ribavirin 1. Introduction with an increased risk of hepatocellular carcinoma [1,2]. Owing to the chronic nature of the disease, estimates Hepatitis C virus (HCV) is the leading cause of liver suggest that its healthcare burden will increase dramat- transplantation in the US and Europe and is associated ically [3]. The current standard of treatment is based on interferon alfa therapy and consists of the combina- tion of peginterferon alfa-2 plus ribavirin [4]. Received 15 August 2005; received in revised form 7 March 2006; Type I interferons do not interact directly with the accepted 9 March 2006; available online 18 April 2006 * Corresponding author. Tel.: +54 2322 482624. virus but rather exert their effects through interaction E-mail address: [email protected] (M. Silva). with their specific receptor. The interaction initiates a 0168-8278/$32.00 Ó 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2006.03.008 M. Silva et al. / Journal of Hepatology 45 (2006) 204–213 205 cascade of intracellular Janus-kinase-mediated events, countries, and the study was conducted according to the Declaration leading to changes in gene-transcript expression. Some of Helsinki and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for of these up-regulated genes [e.g., RNA-dependent pro- Human Use (ICH) Guidance for Good Clinical Practice. Written tein kinase (PKR), 2050 oligoadenylate synthetase informed consent was obtained from all patients prior to conducting (OAS)] are believed to have an important role in the study-related procedures. interruption of HCV replication within infected hepato- 2.2. Patients cytes [5–7]. Recent advances in pegylation chemistry have led to Thirty-six treatment-naı¨ve patients between the ages of 18 and 65 the development of interferon alfas with longer half- years who were infected with HCV genotype 1a or 1b [with a minimum lives. The covalent attachment of a polyethylene glycol of 6.0 · 105 HCV-RNA IU/mL, determined by quantitative polymer- (PEG) molecule to the interferon alfa protein results in ase chain reaction (PCR)] were eligible for enrollment into the study. Additional inclusion criteria were alanine aminotransferase (ALT)/as- decreased renal clearance and a longer half-life in the partate aminotransferase (AST) levels 610 times the upper limit of plasma [8–10]. The size and position of the PEG mole- normal (ULN), normal haemoglobin, white-blood-cell count cule used in the two currently licensed peginterferons: P4000 cells/lL, neutrophil count P1500 cells/lL, and platelet count Ò P100,000/lL. Subjects were excluded from participation if they had peginterferon alfa-2b (PegIntron , Schering Corp., evidence of liver disease due to causes other than chronic HCV infec- Kenilworth, NJ, USA) and peginterferon alfa-2a (Pega- tion, HIV positivity, haemoglobinopathy, haemophilia, severe pre-ex- sysÒ, Hoffmann-La Roche, Basel, Switzerland) differ isting psychiatric disease, poorly controlled diabetes mellitus, significant ischaemic heart disease, chronic obstructive lung disease, significantly in their respective physical-chemical charac- or active autoimmune disease. teristics [11–14]. Although pegylation improves the pharmacokinetic properties of the core protein, it also 2.3. Study endpoints results in loss of in vitro biological activity [8,15]. The antiviral activity of peginterferon alfa-2b is approxi- The primary outcome was to assess the differential impact on inter- mately 28% of the interferon alfa-2b core protein [12]. feron response genes and early viral kinetics of the two peginterferon treatments. Secondary outcome measures included the proportion of The antiviral activity of peginterferon alfa-2a ranges virologic responders (i.e., patients with a P2.0 log10 decrease in between 1% and 7% of the antiviral activity of the inter- HCV-RNA by 8 weeks of peginterferon treatment) as well as the safety feron alfa-2a core protein [16]. Recent work has demon- and tolerability of treatment. strated that the size and site of attachment of the PEG 2.4. Study procedures moiety on the interferon alfa molecule markedly affects its specific activity [12,17]. When subjects met inclusion/exclusion criteria and qualified to The purpose of this trial was to determine if these enter the study, the investigator requested randomisation by faxing in vitro differences between peginterferon alfa-2b and the central randomisation service. Only the site pharmacist responsible peginterferon alfa-2a would translate to observable dif- for medication preparation received confirmation of both the assigned treatment and the subject number. The investigator received the sub- ferences in their in vivo biological activity. This was ject number only. done by assessing the effect of treatment on early viro- Screening evaluations were performed at three independent, research logic response as well as on expression of interferon out-patient clinics. Patients were confined to pharmacology in-patient units on day 1 of week 1 (day 1) and day 1 of week 4 (day 22) for response genes as markers of their mechanism of action approximately 72 h while pharmacokinetic, pharmacodynamic, and [12,17]. antiviral samples were collected. Laboratory safety tests were performed at the sites, but viral kinetics, interferon pharmacokinetics, and pharmacodynamics were centrally analysed in a blinded fashion. 2. Materials and methods 2.5. Interferon serum concentrations 2.1. Study design Serum interferon samples were drawn at days 1 and 22 immediately before peginterferon administration and at 6, 10, 12, 24, 48, 72, and This was an 8-week, double-blind, randomised, multicentre, paral- 120 h after the dose. The peginterferon serum concentrations were lel-group study comparing the pharmacokinetics, pharmacodynamics, determined in a blinded manner, using a validated immunological and antiviral activity of peginterferon alfa-2b and peginterferon alfa-2a (electrochemiluminescent) assay [18,19] and standards for both alfa peg- in patients infected with HCV genotype 1. Study drug was prepared by interferons. Once the study was unblinded, the values from the appro- a site pharmacist and administered by a qualified, independent third priate standard were reported in pg/mL as per the assigned treatment. party who was blinded to protocol assignments. Neither the pharma- cist nor the individual administering the injection had further involve- ment in the study. 2.6. Interferon-alfa response-gene-transcript analysis Patients eligible for the study were randomised to receive once- weekly subcutaneous injections of either peginterferon alfa-2b 1.5 Blood samples for determination of interferon-stimulated gene reg- lg/kg or peginterferon alfa-2a 180 lg for 8 weeks. After the fourth ulation were collected into PAX-Gene tubes (Becton–Dickinson, week of treatment, oral ribavirin therapy was added to the regimen Franklin Lakes, NJ, USA) prior to the first dose and at 6, 24, 48, at a dose of 13 mg/kg, in a divided BID dose. At the end of the study and 72 h after the first dose of peginterferon. Samples were
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