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Pharmacology of Interferon

Interferon

Natural Interferons

Man Made Interferons (Recombinant)

Interferon Basics
• Interferons play an important role in the first line of defense against viral infections
• Interferons are part of the non-specific immune system • Interferons are made by cells in response to an appropriate stimulus

Types on Interferon • alpha (leukocyte interferon) – produced by virus infected leukocytes • beta (fibroblast interferon) – produced by virus infected fibroblasts or epithelial cells • gamma (immune interferon) – produced by certain activated T cells & NK cells .

How Does It Prevent Viral Replication? virus cells (Other stimuli: exogenous ds RNA. bacterial components) . LPS.

How Does It Prevent Viral Replication? virus interferon .

How Does it Prevent Viral Replication? No replication virus Inhibitory proteins .

Interferon Response to Acute Viral Infection .

Effects of Interferon Treatment .

Mechanisms of Action • IFN alpha and beta – induction of inhibitory protein synthesis • IFN gamma – inc class II MHC molecules of APC – Inc ability of macrophages to resist viral infx and kill other cells if infected • All IFN – inc class I MHC molecules – inc activity of NK cells .

Viral Defense Against Interferon • block interferon binding to cells • inhibit action of interferon-induced protein kinase • inhibit NK function • interfere with cell surface expression MHC • block complement activation • prevent apoptosis in host cell .

Chronic myeloid leukemia. low grade lymphomas.Indications for Interferon • alpha – Hepatitis B & C. Melanoma • beta – Multiple Sclerosis. Hairy cell leukemia. (Ulcerative colitis) . multiple myeloma. Kaposi’s Sarcoma.

Chronic Myeloid Leukemia.Indications for Interferon • gamma – Chronic granulomatous disease. Renal cell Carcinoma .

etc .Incomplete List of Interferons • • • • • • • Actimmune Alferon Avonex Betaserone Infergen Intron Wellferon.

HCV Epidemiology • HCV is leading cause of liver disease • 4 million Americans have been exposed – approx 3 million are infected • HCV infection leads to decompensated cirrhosis and hepatocellular carcinoma • HCV-related cirrhosis is the most common reason for OLT in the US NIH Consensus Development Conference Statement 2002 .

Distribution of HCV .

comorbidities (depression. consume alcohol. HIV coinfections) – pegylated interferon with ribiviran better than peginterferon monotherapy or standard interferon-ribivarin .Management of Hepatitis C • Consensus Statement in 2002 – treatment eligible patients • IVD users.

HCV Infection .

Interferon in Hepatitis C • Monotherapy – standard interferon 3 Million units inj tiw (Low Sustained virologic response) • Combination therapy – standard interferon with ribivarin – pegylated interferon with ribivarin .

Interferon in HCV • Limitations – monotherapy not very effective – cumbersome dosing (TIW) – multiple side effects .

diarrhea Depression. vomiting. partial alopecia Hematologic abnormalities Autoimmune disorders .Interferon Side Effects (Hepatitis C Data) • • • • • • • Flu-like symptoms Headache Nausea. irritability. anxiety Injection site reactions.

“monitor patients for depression and prescribe antidepressants when necessary” • Hematologic abnormalities – neutropenia and thrombocytopenia • treatment options include decreasing dose or giving hematopoietic growth factors . Lancet 2001) – NIH consensus .Management of Side Effects • Depression (77% Manns et al.

Pegylated Interferon • HCV is an ideal setting for peginterferon – polyethylene glycol (PEG):interferon • Pegylation was developed to overcome disadvantages of standard interferon – shields IFN from enzymatic degradation thus lowers systemic clearance – allows less frequent dosing – achieve higher/sustained serum [interferon] .

Fried et al: Peginterferon Alfa-2a Plus Ribavirin 60% 50% 40% 56% 44% 29% monotherapy IFN+RBV Peg+RBV 30% 20% 10% 0% Pega2a IFN a2b+RBV Pega2aRBV P=<0.001 .

branched molecule – weight 40 kDa .Differences in PEG • peginterferon alfa-2b – linear molecule – weight 12 kDa • peginterferon alfa-2a – larger.

Peginterferon .

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Pharmacologic Parameters of Peginterferons Peg alfa-2b Volume of distribution Absorption half-life (h) Mean elimination half-life (h) Peg alfa-2a 8L 50 80 20 L 4.6 40 .

5 mcg/kg/week) – high volume of distribution • kidney.Weight-Based Dosing and Peginterferon Therapy • Once weekly dosing • alfa 2b – weight based dosing (1-1. liver and throughout the bloodstream • alfa 2a – fixed dose at 180 mcg/week – low volume of distribution . heart.

Conclusions • Interferons are important in the nonspecific immune response • Interferons are effective in the treatment of patients with chronic hepatitis • Pegylated interferons are superior therapies for patients with HCV • Side effects should be monitored closely .

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