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, LPS, bacterial components)

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

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)

Indications for Interferon

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

Incomplete List of Interferons

Actimmune Alferon Avonex Betaserone Infergen Intron Wellferon, etc

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

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

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

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

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

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

Differences in PEG
peginterferon alfa-2b
linear molecule weight 12 kDa

peginterferon alfa-2a
larger, branched molecule weight 40 kDa

Peginterferon

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

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

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