Pharmacology of Interferon

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PharmacologyofInterferon
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Interferon
Natural Interferons
Man Made Interferons (Recombinant)
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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

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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

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How Does It Prevent Viral Replication?
virus
cells
(Other stimuli exogenous ds RNA, LPS, bacterial
components)
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How Does It Prevent Viral Replication?
virus
interferon
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How Does it Prevent Viral Replication?
No replication
virus
Inhibitory proteins
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Interferon Response to Acute Viral Infection
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Effects of Interferon Treatment
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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

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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

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Indications for Interferon

• alpha
• Hepatitis B C, Hairy cell leukemia, Chronic
  myeloid leukemia, multiple myeloma, low grade
  lymphomas, Kaposis Sarcoma, Melanoma
• beta
• Multiple Sclerosis, (Ulcerative colitis)

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Indications for Interferon

• gamma
• Chronic granulomatous disease, Chronic Myeloid
  Leukemia, Renal cell Carcinoma

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Incomplete List of Interferons

• Actimmune
• Alferon
• Avonex
• Betaserone
• Infergen
• Intron
• Wellferon, etc

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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
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Distribution of HCV
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Management of Hepatitis C

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

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HCV Infection
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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

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Interferon in HCV

• Limitations
• monotherapy not very effective
• cumbersome dosing (TIW)
• multiple side effects

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Interferon Side Effects
(Hepatitis C Data)

• Flu-like symptoms
• Headache
• Nausea, vomiting, diarrhea
• Depression, irritability, anxiety
• Injection site reactions, partial alopecia
• Hematologic abnormalities
• Autoimmune disorders

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Management of Side Effects

• Depression (77 Manns et al, Lancet 2001)
• NIH consensus - monitor patients for depression
  and prescribe antidepressants when necessary
• Hematologic abnormalities
• neutropenia and thrombocytopenia
• treatment options include decreasing dose or
  giving hematopoietic growth factors

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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

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Fried et al Peginterferon Alfa-2a Plus Ribavirin
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Plt0.001
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Differences in PEG

• peginterferon alfa-2b
• linear molecule
• weight 12 kDa
• peginterferon alfa-2a
• larger, branched molecule
• weight 40 kDa

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Peginterferon
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Pharmacologic Parameters of Peginterferons
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Weight-Based Dosing and Peginterferon Therapy

• Once weekly dosing
• alfa 2b
• weight based dosing (1-1.5 mcg/kg/week)
• high volume of distribution
• kidney, heart, liver and throughout the
  bloodstream
• alfa 2a
• fixed dose at 180 mcg/week
• low volume of distribution

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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