Pharmacology of Interferon Downloaded from

Interferon Natural Interferons Man Made Interferons (Recombinant) Downloaded from

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 Downloaded from

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 Downloaded from

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

How Does It Prevent Viral Replication? virus interferon Downloaded from

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

Interferon Response to Acute Viral Infection Downloaded from

Effects of Interferon Treatment Downloaded from

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 Downloaded from

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 Downloaded from

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) Downloaded from

Indications for Interferon gamma –Chronic granulomatous disease, Chronic Myeloid Leukemia, Renal cell Carcinoma Downloaded from

Incomplete List of Interferons Actimmune Alferon Avonex Betaserone Infergen Intron Wellferon, etc Downloaded from

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 Downloaded from

Distribution of HCV Downloaded from

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 Downloaded from

HCV Infection Downloaded from

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 Downloaded from

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

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) Downloaded from

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 Downloaded from

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] Downloaded from

Fried et al: Peginterferon Alfa-2a Plus Ribavirin P=< % 44% 56% Downloaded from

Differences in PEG peginterferon alfa-2b –linear molecule –weight 12 kDa peginterferon alfa-2a –larger, branched molecule –weight 40 kDa Downloaded from

Peginterferon Downloaded from

Pharmacologic Parameters of Peginterferons Downloaded from

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 Downloaded from

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 Downloaded from