Transcript Interferon Therapy

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, 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
(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
56%
60%
44%
50%
40%
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
Peg alfa-2a
20 L
8L
Absorption half-life
(h)
4.6
50
Mean elimination
half-life (h)
40
80
Volume of
distribution
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