Pharmacology of Interferon. Interferon Natural Interferons Man Made Interferons (Recombinant)

Pharmacologyof

Interferon

Interferon

NaturalInterferons

Man MadeInterferons

(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?

virus

Inhibitoryproteins

No replication

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, Kaposi’s 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

• Flu-like symptoms

• Headache

• Nausea, vomiting, diarrhea

• Depression, irritability, anxiety

• Injection site reactions, partial alopecia

• Hematologic abnormalities

• Autoimmune disorders

(Hepatitis C Data)

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

0%

10%

20%

30%

40%

50%

60%

Pega2a IFN a2b+RBV Pega2aRBV

monotherapyIFN+RBVPeg+RBV

P=<0.001

29%

44%

56%

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 Peg alfa-2a

Volume ofdistribution

20 L 8 L

Absorption half-life(h)

4.6 50

Mean eliminationhalf-life (h)

40 80

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