Introduction to Clinical Pharmacy

Biological Immunomodulators in Therapeutics

Keith T. Veltri, BPharm., PharmD.

Assistant Professor
Touro College of Pharmacy
Review of Hematological Terminology
• White blood cells (WBCs), or leukocytes , are cells of the
immune system defending the body against both infectious
disease and foreign materials. Five different and diverse types
of leukocytes exist, but they are all produced and derived
from a multipotent cell in the bone marrow known as a
hematopoietic stem cell. Leukocytes are found throughout
the body, including the blood and lymphatic system.
• The number of leukocytes in the blood is often an indicator of
disease. There are normally between 4×109 and 1.1×1010
white blood cells in a liter of blood, making up approximately
1% of blood in a healthy adult.
• An increase in the number of leukocytes over the upper limits
is called leukocytosis, and a decrease below the lower limit is
called leukopenia.
 Review of Hematological Terminology
• There are several different types of white blood cells. They all have many
things in common, but are all different. A major distinguishing feature of
some leukocytes is the presence of granules; white blood cells are often
characterized as granulocytes or agranulocytes:
• Granulocytes (polymorphonuclear leukocytes): leukocytes characterized
by the presence of differently staining granules in their cytoplasm when
viewed under light microscopy. These granules are membrane-bound
enzymes which primarily act in the digestion of endocytosed particles.
There are three types of granulocytes: neutrophils, basophils, and
eosinophils, which are named according to their staining properties.
• Agranulocytes (mononuclear leucocytes): leukocytes characterized by the
apparent absence of granules in their cytoplasm. Although the name
implies a lack of granules these cells do contain non-specific azurophili
granules, which are lysosomes. The cells include lymphocytes, monocytes,
and macrophages.
Review of Hematological Terminology
• Red blood cells (also referred to as erythrocytes) are the
most common type of blood cell and the vertebrate body's
principal means of delivering oxygen to the body tissues via
the blood. They take up oxygen in the lungs or gills and
release it while squeezing through the body's capillaries.
• The cells are filled with hemoglobin, a biomolecule that can
bind to oxygen. The blood's red color is due to the color of
oxygen-rich hemoglobin. In humans, red blood cells develop
in the bone marrow and live for about 120 days; they take the
form of flexible biconcave disks that lack a cell nucleus and
organelles and they cannot synthesize protein.
 Review of Hematological Lab Indices
• Adult humans have roughly 2–3 × 1013 red blood cells at any given time
(women have about 4 to 5 million erythrocytes per microliter (cubic millimeter)
of blood and men about 5 to 6 million; people living at high altitudes with low
oxygen tension will have more).
• Total red blood cells - The number of red cells is given as an absolute number
per liter.
– Hemoglobin - The amount of hemoglobin in the blood, expressed in grams
per deciliter. (Low hemoglobin is called anemia.)
Normal results vary, but in general are:
• Male: 13.8 to 17.2 gm/dL
• Female: 12.1 to 15.1 gm/dL
– Hematocrit or packed cell volume (PCV) - This is the fraction of whole
blood volume that consists of red blood cells.
• Red blood cells are thus much more common than the other blood particles:
there are about 4,000–11,000 white blood cells and about 150,000–400,000
platelets in each microliter of human blood.
• The red blood cells of an average adult human male store collectively about 2.5
grams of iron, representing about 65% of the total iron contained in the body
 Review of Hematological Lab Indices
• A complete blood count will normally include: red blood cells
(total RBCs, hemoglobin and hematocrit), white blood cells
(with differential) and platelet count.
Introduction
• Adequate blood cell production and
development (hematopoiesis) and immune
system function (immunocompetence) are
vital processes in the human body’s ability to
fight harmful invaders
• Inadequate or impaired hematopoiesis or
immune function (immunodeficiency) leads
to high risks for infection and cancer
 Introduction
• Extensive research has been performed to
develop drugs that “modify” the immune system
• These pharmacological agents are often referred
to as immunomodulators or biologic response
modifiers.
• Classified as:
1. Immunostimulants
2. Immunosuppressives
 Introduction
• Cytokines are any of a number of substances that
are secreted by specific cells of the immune system
• Cytokines are diverse substances produced mainly
by bone marrow and white blood cells that regulate
many cellular activities by acting as chemical
messengers and as growth factors for blood cells
• The main group of hematopoietic cytokines are
classified as: colony-stimulating factors (CSFs),
interferons or interleukins
Colony-Stimulating Factors
(CSFs)
• Colony-stimulating factors (CSFs) are secreted
glycoproteins which bind to receptor proteins on the
surfaces of hemopoietic stem cells and thereby activate
intracellular signaling pathways which can cause the cells
to proliferate and differentiate into a specific kind of blood
cell
• CSFs stimulate the production of red blood cells
(erythropoietin), platelets (thrombopoietin), granulocyte
neutophils, basophils and eosinophils (G-CSF),
granulocyte eosinophils, basophils and monocytes
macrophages (GM-CSF) or monocyte macrophages (M-
CSF)
Classification and Individual Drugs
1. Immune stimulants are drugs used to “energize” the
immune system when it is exhausted from fighting
prolonged invasion or needs assistance in fighting a
specific pathogen or cancerous cell
• Most hematopoietic/immunostimulant drugs are synthetic versions
of endogenous cytokines
• Several products are commercially available and produced by
recombinant DNA technology which involves identifying the genes
responsible for producing these substances
• These genes are then inserted into bacteria (usually Escherichia
coli) or yeasts capable of producing these substances exogenously
• Drugs available for therapeutic use are the hematopoietic colony-
stimulating factors (CSFs) including: darbopoeitin alfa, epoetin alfa,
filgrastim and sargramostim), several interferons, and two
interleukins
Darbepoetin alfa (Aranesp®) and epoetin
alfa (Epogen®, Procrit®),
• Hematopoietic agents that are drug formulations of
erythropoeitin, a hormone from the kidney that stimulates
bone marrow production of red blood cells.
• Erythropoeitin is a cytokine for erythrocyte (red blood
cell) precursors in the bone marrow.
• Used to prevent or treat anemia associated with several
conditions including chronic renal failure and
myelosuppressive chemotherapy (depresses bone
marrow function)
• These drugs raise the hemoglobin and reduce the need
for blood transfusions in many patients that are anemic
The Effects of erythropoeitin
Darbepoetin alfa (Aranesp®) and epoetin
alfa (Epogen®, Procrit®),
• In chronic renal failure, epoetin has a serum half-
life of 4 to 13 hours and produces detectable blood
levels of erythropoietin within 24 hours of IV
administration (longer with Sub Q)
• Darbepoetin has a longer half-life (about 49 hours)
in these patients and peak plasma levels occur in
34 hours
• These drugs raise the hemoglobin and reduce the
need for blood transfusions in many patients that
are anemic
Darbepoetin alfa (Aranesp®) and epoetin
alfa (Epogen®, Procrit®),
• Studies indicate an increased risk for
cardiovascular events (hypertension and
thromboembolic events) and death in patients
with chronic renal failure and an increased risk
for tumor progression and death in patients with
cancer
• These problems became evident when the drugs
were used to achieve normal hemoglobin levels
of 12 to 14 grams per deciliter
BLACK BOX WARNING
• These results led the U.S. Food and Drug
Administration (FDA) to issue this warning in the
drugs packet insert (PI) advising prescribers to
avoid using the drugs in patients with hemoglobin
values of 12 grams per deciliter or above or
increased by more than 1 gram per deciliter in any 2
week period
• These drugs should be initially prescribed at the
lowest dose effective in raising hemoglobin levels
just enough to avoid the need for blood transfusions
Colony-Stimulating Factors
(CSFs)
• Filgrastim (Neupogen®) and sargramostim (Leukine®) are drug
formulations of granulocyte colony-stimulating factor (G-CSF) and
granulocyte macrophage colony stimulating factor (GM-CSF),
respectively
• Used to stimulate blood cell production by the bone marrow in patients
in bone marrow transplantation, Hodgkin’s disease, non-Hodgkin’s
lymphoma, acute lymphostatic leukemia or chemotherapy-induced
neutropenia (low WBC count with neutrophil count < 1000/mm 3; severe
< 500/mm3 )
• G-CSF is also used to collect stem cells for transplantation, and GM-
CSF is also used to promote growth of blood vessels (angiogenesis) in
patients with ischemic heart disease.
• When used to stimulate blood cell production, the drugs
should be discontinued when blood cell counts normalize
Colony-Stimulating Factors
(CSFs)
• Before receiving a bone marrow transplant, the patient’s
immune system is suppressed by anticancer drugs or
radiation. After transplantation, it take 2-4 weeks for
bone marrow cells to mature and begin producing blood
cells
• Neutropenic patients are at high risk for bacterial, fungal
and viral infections which often result from the normal
microbial flora of the patient or environmental factors
• These drugs can reduce the incidence and severity of
infections in neutropenic patients
Colony-Stimulating Factors
(CSFs)
• When filgrastim is administered to prevent infection in neutropenic
patients with cancer, the drug should be initiated at least 24 hours after
the last dose of the antineoplastic agent and continued during the period
of bone marrow suppression and recovery
• CBC and platelet counts should be performed twice weekly during
therapy and the drug should be discontinued if the neutrophil count
exceeds 10,000/mm3. Pegfilgrastim should not be given between 14
days before and 24 hours after chemotherapy
• When sargramostim is given to patients with cancer who have had bone
marrow transplantation, the drug should be started 2-4 hours after the
bone marrow infusion and at least 24 hours after the least 24 hours after
the last dose of chemotherapy or 12 hours after the last radiotherapy
treatment . CBC should be performed twice weekly during therapy, and
the neutrophil count should not exceed 20,000mm 3
Colony-Stimulating Factors
(CSFs)
• Filgrastim is conjugated with polyethylene glycol,
in a process caused pegylation, to produce
pegfilgrastim (Neulasta®), a formulation which
remains longer in the body systemically and can
be administered less often than filgrastim
• Significant adverse effects for CSFs (depending
on specific agent) include nausea, vomiting,
constipation or diarrhea, mucositis, fluid
retention (peripheral edema, pleural effusion,
pericardial effusion) and bone pain
Colony-Stimulating Factors
(CSFs)
The Interleukins (ILs)
• Interleukins are a group of cytokines that were first seen to be expressed by
white blood cells. It has since been found that interleukins are produced by a
wide variety of body cells
• The function of the immune system depends in a large part on interleukins,
and rare deficiencies of a number of them have been described, all featuring
autoimmune diseases or immune deficiency
• The majority of interleukins are synthesized by helper CD4+ T lymphocytes,
as well as through monocytes, macrophages, and endothelial cells. They
promote the development and differentiation of T, B, and hematopoietic cells
• Eighteen interleukins have been characterized and more have been identified
• Especially important ILs include IL-3 (stimulates growth of stem-cell
precursors of all blood cells), IL-2 (stimulates T and B lymphocytes), IL-12
(stimulates hematopoietic cells and lymphocytes) and IL-11 (stimulates
platelets and other cells)
• Two interleukin preparations are available for use
Aldesleukin (Proleukin®)

• A recombinant DNA version of interleukin-

2 (IL-2) that activates cellular immunity;
produces tumor necrosis factor,
interleukin-1 (IL-1), and interferon gamma
 inhibits tumor growth
• Used to treat metastatic kidney cancer and
metastatic melanoma skin cancer
• Contraindicated in preexisting
cardiovascular and pulmonary impairment
Oprelvekin (Neumega®)

• A recombinant IL-11, which

stimulates platelet production
• Used to prevent thrombocytopenia
and reduce the need for platelet
transfusions in patients with cancer
who are receiving myelosuppressive
chemotherapy
The Interferons
•Naturally produced and
released by human cells
that have been invaded
by viruses or in response
to other stimuli
•Interferons act to prevent
virus particles from
replicating inside other
cells
•Stimulate interferon
receptor sites on non-
invaded cells to promote
the production of anti-viral
proteins, which will
prevent viruses from
entering the cell
•Inhibit tumor growth and
replication
 The Interferons
Generic/Trade Name Indications for Use
Interferon alfa-2a/ Chronic hepatitis C in adults, hairy cell leukemia in adults,
Roferon-A® AIDS-related Kaposi’s sarcoma in adults, chronic
myelogenous leukemia (CML)
Peginterferon alfa-2a/ Chronic hepatitis B
Pegasys® Chronic hepatitis C (alone or with ribavirin)
Peginterferon alfa -2b/ Chronic hepatitis C, alone or with ribavirin
PEG-Intron®
Interferon alfa-2b/ Hairy cell leukemia in adults, AIDS related Kaposi’s sarcoma
Intron-A® in adults, Condylomata (genital warts) caused by HPV,
Chronic hepatitis B and C (alone or with ribavirin), Malignant
melanoma (after surgical excision) and Non-Hodgkin’s
lymphoma
Interferon alfacon-1/ Chronic hepatitis C in adults
Infergen®
Interferon beta-1a/ Multiple sclerosis to reduce frequency of exacerbations
Avonex®
Interferon beta-1b/ Same as Interferon beta-1a
Betaseron®
Interferon gamma-1b/ Reducing frequency and severity of serious infections
Actimmune® associated with chronic myelogenous leukemia
The Interferons
• For certain clinical uses, the older
preparations of interferon alfa have also been
largely replaced through pegylation to
produce peginterferon alfa
• Peginterferons are administered less often
and provide more constant blood levels when
compared to unpegylated interferons
Adverse Effects
• Main side effects are flu-like symptoms,
interferons may also cause or aggravate
serious, life-threatening neuropsychiatric
(including depression and some reports of
suicide), autoimmune, ischemic and infectious
disorders and increased LFTs
• In many cases, these disorders resolve after
discontinuing therapy
Laboratory Monitoring
• When darbepoetin and epoetin, iron stores (transferrin saturation and
serum ferritin) should be measured before and periodically during
treatment. Adequate intake of iron is required for drug effectiveness and
an iron supplement is usually necessary
• Hemoglobin should be measured twice weekly until stabilized and
maintenance drug doses are established
• With most of the hematopoietic agents and immunostimulant drugs, a
CBC with WBC differential and platelet count should be performed before
and during treatment to monitor response and prevent avoidable adverse
reactions
• With CSFs, these tests are recommended twice weekly during drug
administration ; with interferons, tests for platelet and neutrophil counts,
hemoglobin, serum creatinine, serum albumen and thyroid stimulating
hormone are recommended for all patients before starting therapy, 2
weeks later and periodically thereafter throughout the course of therapy
Drug Administration
• Hematopoietic and immunostimulant
agents are administered either
subcutaneous (Sub-Q), intravenous (IV)
injection (or intramuscularly (IM)
• The hematopoietic agents and the
interferons can be self- or caregiver
administered to ambulatory patients while
the interleukins are highly toxic and must
be administered in the inpatient setting
Biological
Immunostimulants
 Review and Application Exercises
1. Interferon may be used to treat:
A. most types of cancer
B. chronic hepatitis C
C. flu-like symptoms
D. mental depression

2. The expected outcome of administering epoetin alfa

(Epogen®, Procrit®) or darbepoetin alfa (Aranesp®) to a
patient with chronic renal failure is:
A. decreased bleeding
B. increased WBC production
C. increased RBC production
D. improved renal function
 Review and Application Exercises
3. The pharmacist is monitoring a patient who is undergoing
chemotherapy for cancer. Filgrastim (Neupogen®) is ordered. The pharmacist
explains to the patient that an expected outcome after drug administration is:
A. fewer infections
B. decreased anemia
C. longer life expectancy
D. less nausea and vomiting

4. The pharmacist who is dispensing epoetin or darbepoetin knows that most patients who
take these drugs also need to take:
A. iron
B. potassium
C. antacids
D. Analgesics
Classification and Individual Drugs
2. Immune suppressants are used to block the normal
effects of the immune system in cases of organ transplant
and in autoimmune disorders; interfere with the production
or function of immune cells and cytokines
• Like the immunostimulants, several products are commercially
available and produced by recombinant DNA technology which
involves identifying the genes responsible for producing these
substances
• Used to treat inflammatory autoimmune disorders or transplant
rejection reactions
• Most immunosuppressive biological agents are administered either
subcutaneous (Sub-Q), intravenous (IV) injection or intramuscularly
(IM) with the exception of leflunomide which is oral
• Ambulatory or inpatient setting depending on specific agent
Autoimmune Disorders
• Autoimmune disorders have been associated with:
1. Excessive amount of the cytokine TNF alpha (tumor necrosis factor)
which plays a major role in the immune response activation
• Functions include activation of monocytes, macrophages and
cytotoxic T cells; enhancement of natural killer (NK) cell functions;
increased leukocyte movement into areas of tissue injury;
increased phagocytosis by neutrophils ; and stimulation of B and T
lymphocytes
2. Inadequate number of anti-inflammatory cytokines (i.e [IL]-10)
• Allergic asthma, Crohn’s disease, psoriasis, psoriatic arthritis
and rheumatoid arthritis are inflammatory autoimmune
disorders that may be treated with immunosuppressant drugs
Tissue and Organ Transplantation
• Drug-induced immunosuppression is a major part of protocols to
prevent graft rejection reactions with solid organ transplantation, and
graft versus host disease (GVHD) with bone marrow/stem cell
transplantation
• Rejection reactions manifested as solid organ failure are categorized as:
a) Acute (10 days to a few months) and mainly involve cellular
immunity and proliferation of T lymphocytes
b) Chronic (months or years of normal function) and mainly involve
both cellular and humoral immunity
• Acute GVHD occurs in 30% to 50% of patients, usually within 6 weeks
whereas chronic GVHD occurs when symptoms persist 100 days or
more after transplantation
Antibody Preparations
• Antibody (immunoglobulin) preparations are
classified as polyclonal or monoclonal
• Polyclonal preparations are a mixture of antibodies
(IgA, IgD, IgE, IgG, IgM ) produced by several clones
of B lymphocytes
• Antithymocyte globulin (ATG) is a nonspecific
immune globulin that contains antibodies that
destroy lymphoid tissues and decrease the number
of circulating T cells
 Biological Immunosuppressants
Polyclonal Antibody Indications for Use

ATG (equine:Atgan) Used to treat renal

transplant rejection
reactions and aplastic
anemia in patients who are
not considered candidates
for bone marrow
transplantation
ATG (rabbit: Used to treat renal
Thymoglobulin) transplant rejection
reactions
Antibody Preparations
• Monoclonal antibodies are produced
through isolation and clone of individual
B lymphocytes resulting in the
production of identical antibody
molecules
 Biological Immunosuppressants
Monoclonal Antibody Indications for Use

Alefacept ( Amevive®) Psoriasis

Basiliximab (Simulcet®) Prevent renal transplant rejection

Daclizumab ( Zenapax®) Prevent renal transplant rejection

Efalizumab (Raptiva®) Psoriasis

Muromonab – CD3 (Orthoclone® OKT3) Treatment of renal, cardiac and hepatic

transplant rejections
Omalizumab (Xolair®) Allergic asthma
Cytokine Inhibitors
• Two major cytokines in chronic inflammatory
autoimmune disorders are IL-1 and TNF-alpha
• Suppress inflammation and promote tissue repair in
autoimmune disorders
• Despite their therapeutic effects, these agents
increase the risk of serious infections, (especially the
TNF-alpha inhibititors) including tuberculosis,
pneumococcal infections, necrotizing fascitis,
Pneumocystis pneumonia and systemic fungal
infections such as aspergillosis and crytptococcus
Cytokine Inhibitors
• To decrease the adverse effects of the TNF inhibitors,
the following guidelines have been developed for
patients receiving these drugs:
 Tuberculin testing before initiation of TNF
inhibitor and anti-tubercular prophylaxis for
patients with positive skin tests results
Administration of pneumococcal and
meninogococcal vaccine
Administration of trimethoprim-sulfamethoxazole
(TMP-SMX) to prevent infection
Cytokine Inhibitors
 Consideration of fluconazole administration to
patients at high risk of developing
coccidioidomycosis and cryptococcus
 Education of patients and caregivers to avoid
potential exposures to infection in the community
 Provision of antibiotics for immediate initiation at
home with the onset of fever or upper
respiratory infection, followed by seeking
emergency care
 Biological Immunosuppressants

Interleukin Blocking Agents TNF -alpha Blocking Agents

Il-1 Blocking Agent Indications for Use TNF-alpha Blocking Indications for
Agent Use

Anakinra Rheumatoid arthritis Adalizumab (Humira®) Rheumatoid Arthritis

(Kineret®) Certolizumab Crohn’s disease
(Cimizia®)
Etanercept (Enbrel®) Rheumatoid arthritis,
psoriatic arthritis,
ankylosing spondylitis,
Juvenile chronic arthritis
Infliximab Crohn’s disease,
(Remicade®) rheumatoid arthritis,
psoriasis
Golimumab (Simponi® Rheumatoid arthritis,
psoriatic arthritis,
ankylosing spondylitis
 Biological Immunosuppressants
Miscellaneous Agents
Generic /Trade Name Mechanism of Action Indications for Use

Abatacept /(Orencia®) Inhibits activation of T Rheumatoid Arthritis

lymphocytes in synovial
membranes of joints
decreasing inflammation

Leflunomide /(Arava®) Inhibits components of Rheumatoid Arthritis

DNA and RNA and
therefore blocks T cells via
anti-proliferative and anti-
inflammatory properties
Biological
Immunosuppressants
 Review and Application Exercises
1. In addition to organ transplantation,immunosuppressant drugs are used
to treat:
A. serious infections
B. Crohn’s disease and rheumatoid arthritis
C. gastroesophageal reflux disease (GERD)
D. seizure disorders

2. Remicade® is a tissue necrosis factor blocking agent used in the

treatment of:
A. asthma
B. psoriasis
C. Crohn’s disease
D. B and C
 Review and Application Exercises
3. Patients taking immunosuppressant drugs should be taught:
A. methods to decreased infections
B. to avoid weight gain
C. to maintain proper fluid intake
D. to increased rest and decrease exercise

4. Antithymocyte globulin (ATG) is a polyclonal antibody used to

treat:
A. Neutropenia
B. Renal transplant rejection
C. AIDS related Kaposi’s Sarcoma
D. Multiple sclerosis
 Answer Key
Section 1 Section 2
1. B 1. B
2. C 2. D
3. A 3. A
4. A 4. B
 References
1. Abrams, A.C., et. al. (2009). Clinical Drug Therapy
(9th ed.). Pennsylvania: Lippincott Williams & Wilkins
2. Gilman, A. , Hardman, J.G., & Limbird, L.E. (Eds.).
(2002). Goodman and Gilman’s The Pharmacological
Basis of Therapeutics (10th ed.). New York: McGraw
–Hill
3. The Medical Letter on Drugs and Therapeutics.
(2004). New Rochelle, NY: Medical Letter
4. www.medpedia.com