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DOI: 10.1055/s-2003-41631
Pharmacokinetics of Peginterferons
Publikationsverlauf
Publikationsdatum:
21. August 2003 (online)
ABSTRACT
Two polyethylene glycol (PEG)-modified interferons are approved for the treatment of chronic hepatitis C. The pharmocokinetic properties of the branched 40 kDa pegylated interferon alfa-2a differ from the linear 12 kDa pegylated interferon alfa-2b. The absorption half-life of standard interferon alfa is 2.3 hours, while absorption half-lives for peginterferon alfa-2a and alfa-2b are 50 hours and 4.6 hours, respectively. The volume of distribution for peginterferon alfa-2a is considerably restricted, while the volume of distribution for peginterferon alfa-2b is only approximately 30% lower than that for conventional interferon. Because of its large size, the 40 kD peginterferon alfa-2a has a more than 100-fold reduction in renal clearance compared with conventional interferon alfa. Clearance of peginterferon alfa-2b is about one-tenth that of unmodified interferon alfa. Although data are limited, both drugs appear to show differences in the initial viral decay pattern in patients with chronic hepatitis C. However, it remains unknown whether these differences in the initial viral decline predict differences in the primary clinical endpoint, sustained virological response.
KEYWORDS
Peginterferon alfa-2a - peginterferon alfa-2b - pharmacokinetics - viral kinetics
REFERENCES
- 1 Harris J M, Martin N E, Modi M. Pegylation. A novel process for modifying pharmacokinetics. Clin Pharmacokinet . 2001; 40 539-551
- 2 Delgado C, Francis G E, Fisher D. The uses and properties of PEG-linked proteins. Critical Reviews in Therapeutic Drug Carrier Systems . 1992; 9 249-304
- 3 Pestka S, Langer J A, Zoon K C, Samuel C E. Interferons and their actions. Annu Rev Biochem . 1987; 56 727-777
- 4 Wills R J. Clinical pharmacokinetics of interferons. Clin Pharmacokinet . 1990; 19 390-399
- 5 Monkarsh S P, Ma Y, Aglione A. et al . Positional isomers of monopegylated interferon alpha-2a: isolation, characterization, and biological activity. Anal Biochem . 1997; 247 434-440
- 6 O'Brian C, Pockros P, Reddy R. et al . A double-blind, multicenter, randomized, parallel dose-comparison study of six regimens of 5 kD, linear peginterferon alfa-2a compared with Roferon-A in patients with chronic hepatitis C. Antiviral Therapy . 1999; 4(Suppl) 27
- 7 Grace M, Youngster S, Gitlin G. et al . Structural and biologic characterization of pegylated recombinant IFN-α2b. J Interferon Cytokine Res . 2001; 21 1103-1115
- 8 Glue P, Rouzier-Panis R, Raffanel C. et al . A dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C. Hepatology . 2000; 32 647-653
- 9 Glue P, Fang J, Rouzier-Panis R. et al . Pegylated interferon alfa-2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Clin Pharmacol Ther . 2000; 68 556-567
- 10 Lindsay K L, Trepo C, Heintges T. et al . A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology . 2001; 34 395-403
- 11 Peginterferon alfa-2b product monograph. Kenilsworth, NJ: Schering-Plough 2001
- 12 Bailon P, Palleroni A, Schaffer C A. et al . Rational design of a potent, long-lasting form of interferon: a 40 kDa branched polyethylene glycol-conjugated interferon α-2a for the treatment of hepatitis C. Bioconjug Chem . 2001; 12 195-202
- 13 Algranati N E, Sy S, Modi M. A branched methoxy 40 kDa polyethylene glycol (PEG) moiety optimizes the pharmacokinetics (PK) of peginterferon α-2a (PEG-IFN) and may explain its enhanced efficacy in chronic hepatitis C (CHC) (Abst). Hepatology . 1999; 30(Suppl) 190A
- 14 Modi M W, Fried M, Reindollar R W. et al . The pharmacokinetic behavior of pegylated (40 kDa) interferon alfa-2a in chronic hepatitis C after multiple dosing (Abst). Hepatology . 2000; 32(Suppl) 394A
- 15 Peginterferon alfa-2a product monograph. Nutley, NJ: Hoffman-La Roche 2002
- 16 Heathcote E J, Pockros P J, Fried M W. et al . The pharmacokinetics of pegylated-40K interferon alfa-2a (PEG-IFN) in chronic hepatitis C (CHC) patients with cirrhosis (Abst). Gastroenterology . 1999; 116(Suppl) A735
- 17 Modi M W, Fulton J S, Buckmann D K. et al . Clearance of pegylated (40kDa) interferon alfa-2a is primarily hepatic (Abst). Hepatology . 2000; 32(Suppl) 371A
- 18 Martin P, Mitra S, Farrington K. et al . Pegylated (40kDa) interferon alfa-2a is unaffected by renal impairment (Abst). Hepatology . 2000; 32(Suppl) 370A
- 19 Lamb M W, Marks I M, Wynohradnyk L. et al . 40 kDa peginterferon alfa-2a can be administered safely in patients with end-stage renal disease (Abst). Hepatology . 2001; 34(Suppl) 326A
- 20 Martin N E, Modi M W, Reddy K R. Characterization of pegylated (40kDa) interferon alfa-2a in the elderly (Abst). Hepatology . 2000; 32(Suppl) 348A
- 21 Davis G L, Balan V, Sulkowski M S. et al . A phase 1 study to evaluate the pharmacokinetics, safety, and tolerability of escalating doses of a novel recombinant human albumin-interferon α fusion protein (Albuferon) in subjects with chronic hepatitis C (Abst). Hepatology . 2002; 36(Suppl) 285A
- 22 Xu Z-X, Hoffman J, Patel I, Joubert P. Single-dose safety/tolerability and pharmaco-kinetic/pharmacodynamics (PK/PD) following administration of ascending subcutaneous doses of pegylated interferon (PEG-IFN) and interferon α-2a (IFN α-2a) to healthy subjects (Abst). Hepatology . 1998; 28(Suppl) 702A
- 23 Kamal S M, Fehr J, Roesler B. et al . Peginterferon alone or with ribavirin enhances HCV-specific CD4 T-helper 1 responses in patients with chronic hepatitis C. Gastroenterology . 2002; 123 1070-1083
- 24 Herrmann E, Neumann A U, Schmidt J M, Zeuzem S. Hepatitis C virus kinetics. Antivir Ther . 2000; 5 85-90
- 25 Zeuzem S, Herrmann E, Lee J H. et al . Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon alpha2a. Gastroenterology . 2001; 120 1438-1447
- 26 Wang Y-S, Youngster S, Grace M. et al . Structural and biological characterization of pegylated recombinant interferon alpha-2b and its therapeutic implications. Advanced Drug Delivery Reviews . 2002; 54 547-570
- 27 Buti M, Sanchez-Avila F, Lurie Y. et al . Viral kinetics in genotype 1 chronic hepatitis C patients during therapy with 2 different doses of peginterferon alfa-2b plus ribavirin. Hepatology . 2002; 35 930-936
- 28 Bruno R, Debiaggi M, Ciappina V. et al . Hepatitis C virus dynamics during therapy with peginterferon alfa-2a compared with peginterferon alfa-2b in naive patients with chronic hepatitis C (Abst). Hepatology . 2002; 36(Suppl) 206A