Tocilizumab
Encyclopedia
Tocilizumab is an immunosuppressive drug
, mainly for the treatment of rheumatoid arthritis
(RA) and systemic juvenile idiopathic arthritis
, a severe form of RA in children. It is a humanize
d monoclonal antibody against the interleukin-6 receptor
(IL-6R). Interleukin 6
(IL-6) is a cytokine
that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma
and prostate cancer
.
, if other drugs like disease-modifying antirheumatic drug
s (DMARDs) and TNF alpha blockers have proven to be ineffective, or were not tolerated. It can be used as a single medication for patients who do not tolerate methotrexate. The drug slows down the progression of the disease and can improve physical function of patients.
, a rare benign tumor of B cell
s.
.
s (more than 10% of patients), nasopharyngitis (common cold), headache, and high blood pressure (at least 5%). The enzyme alanine transaminase
was also elevated in at least 5% of patients, but in most cases without symptoms. Among the less common side effects were dizziness, various infections, as well as reactions of the skin and mucosae like mild rashes, gastritis
and mouth ulcer
. Rare but severe reactions were gastrointestinal perforation
s (0.26% in six months) and anaphylaxis
(0.2%).
were reduced by 57% after a single dose of tocilizumab, but it it not known whether this is clinically relevant. A possible mechanism is that the elevated IL-6 levels of patients with RA suppress the biosynthesis of various cytochrome P450 enzymes, notably CYP1A2
, CYP2C9
, CYP2C19
and CYP3A4
. Tocilizumab lowers IL-6 and thus normalises cytochrome levels, increasing the metabolization of simvastatin (and possibly other cytochrome metabolised drugs).
s like RA are associated with abnormally high IL-6 levels. Tocilizumab binds soluble as well as membrane bound interleukin-6 receptors, hindering IL-6 from exerting its pro-inflammatory effects.
, Japan, by Tadamitsu Kishimoto in the 1980s. In 1997, Chugai Pharmaceuticals began the clinical development of tocilizumab for the treatment of rheumatoid arthritis. Clinical studies for Castleman's disease and systemic juvenile idiopathic arthritis started in 2001 and 2002, respectively. Hoffmann–La Roche co-developed the drug due to a license agreement in 2003.
Data presented in 2008 showed the effectiveness of tocilizumab in combination therapy with methotrexate for RA treatment.
In further studies, it was effective and generally well tolerated when administered either as monotherapy or in combination with conventional DMARDs in adult patients with moderate to severe rheumatoid arthritis.
In June 2005, tocilizumab was approved in Japan for Castleman's disease. In January 2009, the drug was approved by the European Medicines Agency
(EMA) as RoActemra for the treatment of rheumatoid arthritis under the mentioned restrictions. On 11 January 2010, it was approved by the U.S. Food and Drug Administration (US FDA) as Actemra for the same purpose. Tocilizumab was approved by Australia's Therapeutic Goods Administration
on 27 May 2009 and was listed on the Pharmaceutical Benefits Scheme
from 1 August 2010. The FDA approved tocilizumab for the treatment of systemic juvenile idiopathic arthritis for children from two years of age in April 2011, and the EMA followed in August the same year.
Tocilizumab is marketed by Chugai in some countries, especially in Japan and other Asian countries, and jointly by Chugai and Roche (Hoffmann–La Roche's holding company
) in others, for example Great Britain, France and Germany.
the drug costs £9,295/year for 70 kg patient for RA treatment. Calculations suggest a base‑case incremental cost-effectiveness ratio
(ICER) of £19,870 per incremental quality‑adjusted life years (QALYs) for patients with DMARD resistance.
Immunosuppressive drug
Immunosuppressive drugs or immunosuppressive agents are drugs that inhibit or prevent activity of the immune system. They are used in immunosuppressive therapy to:...
, mainly for the treatment of rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
(RA) and systemic juvenile idiopathic arthritis
Juvenile idiopathic arthritis
Juvenile idiopathic arthritis is the most common form of persistent arthritis in children. JIA is a subset of arthritis seen in childhood, which may be transient and...
, a severe form of RA in children. It is a humanize
Humanize
Humanize may refer to:*Humanize a 2001 album by the British jazz/funk band Big Boss Man*Humanized antibody, a type of monoclonal antibody...
d monoclonal antibody against the interleukin-6 receptor
Interleukin-6 receptor
Interleukin 6 receptor also known as CD126 is a type I cytokine receptor....
(IL-6R). Interleukin 6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
(IL-6) is a cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
and prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
.
Medical uses
The drug is administered by monthly intravenous infusions. An infusion takes about an hour.Rheumatoid arthritis
Tocilizumab is used for the treatment of moderate to severe rheumatoid arthritis, applied in combination with methotrexateMethotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
, if other drugs like disease-modifying antirheumatic drug
Disease-modifying antirheumatic drug
Disease-modifying antirheumatic drugs is a category of otherwise unrelated drugs defined by their use in rheumatoid arthritis to slow down disease progression...
s (DMARDs) and TNF alpha blockers have proven to be ineffective, or were not tolerated. It can be used as a single medication for patients who do not tolerate methotrexate. The drug slows down the progression of the disease and can improve physical function of patients.
Systemic juvenile idiopathic arthritis
The treatment of systemic juvenile idiopathic arthritis is similar to RA treatment: tocilizumab is combined with methotrexate unless the latter is not tolerated. General safety and effectiveness is established for children of two years and older.Castleman's disease
In Japan, tocilizumab is also approved for the treatment of Castleman's diseaseCastleman's disease
Castleman's disease is an uncommon lymphoproliferative disorder that can involve single lymph node stations or...
, a rare benign tumor of B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
s.
Pregnancy and lactation
No clinical studies evaluating the risk for unborn children are available. A study using large doses of tocilizumab in pregnant animals has found an increased likelihood for spontaneous abortion and death of the unborn. It is not known whether the drug is secreted into the breast milk, nor if this would pose a risk for the nursling.Contraindications
The application of tocilizumab is contraindicated during acute infections, as well as under latent tuberculosisTuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
.
Adverse effects
The most common adverse effects observed in clinical trials were upper respiratory tract infectionUpper respiratory tract infection
Upper respiratory tract infections are the illnesses caused by an acute infection which involves the upper respiratory tract: nose, sinuses, pharynx or larynx...
s (more than 10% of patients), nasopharyngitis (common cold), headache, and high blood pressure (at least 5%). The enzyme alanine transaminase
Alanine transaminase
Alanine transaminase or ALT is a transaminase enzyme . It is also called serum glutamic pyruvic transaminase or alanine aminotransferase ....
was also elevated in at least 5% of patients, but in most cases without symptoms. Among the less common side effects were dizziness, various infections, as well as reactions of the skin and mucosae like mild rashes, gastritis
Gastritis
Gastritis is an inflammation of the lining of the stomach, and has many possible causes. The main acute causes are excessive alcohol consumption or prolonged use of nonsteroidal anti-inflammatory drugs such as aspirin or ibuprofen. Sometimes gastritis develops after major surgery, traumatic...
and mouth ulcer
Mouth ulcer
A mouth or oral ulcer is an open sore in the mouth, or rarely a break in the mucous membrane or the epithelium on the lips or surrounding the mouth. The types of mouth ulcers are diverse, with a multitude of associated causes including: physical abrasion, acidic fruit, infection, other medical...
. Rare but severe reactions were gastrointestinal perforation
Gastrointestinal perforation
Gastrointestinal perforation is a complete penetration of the wall of the stomach, small intestine or large bowel, resulting in intestinal contents flowing into the abdominal cavity. Perforation of the intestines results in the potential for bacterial contamination of the abdominal cavity...
s (0.26% in six months) and anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
(0.2%).
Interactions
There are no certain interactions with other drugs. The blood plasma levels of simvastatinSimvastatin
Simvastatin is a hypolipidemic drug used to control elevated cholesterol, or hypercholesterolemia. Simvastatin is a member of the statin class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus.-Medical uses:The primary uses of simvastatin is for the...
were reduced by 57% after a single dose of tocilizumab, but it it not known whether this is clinically relevant. A possible mechanism is that the elevated IL-6 levels of patients with RA suppress the biosynthesis of various cytochrome P450 enzymes, notably CYP1A2
CYP1A2
Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...
, CYP2C9
CYP2C9
Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...
, CYP2C19
CYP2C19
Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
and CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
. Tocilizumab lowers IL-6 and thus normalises cytochrome levels, increasing the metabolization of simvastatin (and possibly other cytochrome metabolised drugs).
Mechanism of action
Besides other functions, interleukin 6 (IL-6) is involved in the development of immunological and inflammatory reactions. Autoimmune diseaseAutoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
s like RA are associated with abnormally high IL-6 levels. Tocilizumab binds soluble as well as membrane bound interleukin-6 receptors, hindering IL-6 from exerting its pro-inflammatory effects.
History
Interleukin 6 and its receptor were discovered and cloned at Osaka UniversityOsaka University
, or , is a major national university located in Osaka, Japan. It is the sixth oldest university in Japan as the Osaka Prefectural Medical College, and formerly one of the Imperial Universities of Japan...
, Japan, by Tadamitsu Kishimoto in the 1980s. In 1997, Chugai Pharmaceuticals began the clinical development of tocilizumab for the treatment of rheumatoid arthritis. Clinical studies for Castleman's disease and systemic juvenile idiopathic arthritis started in 2001 and 2002, respectively. Hoffmann–La Roche co-developed the drug due to a license agreement in 2003.
Data presented in 2008 showed the effectiveness of tocilizumab in combination therapy with methotrexate for RA treatment.
In further studies, it was effective and generally well tolerated when administered either as monotherapy or in combination with conventional DMARDs in adult patients with moderate to severe rheumatoid arthritis.
In June 2005, tocilizumab was approved in Japan for Castleman's disease. In January 2009, the drug was approved by the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
(EMA) as RoActemra for the treatment of rheumatoid arthritis under the mentioned restrictions. On 11 January 2010, it was approved by the U.S. Food and Drug Administration (US FDA) as Actemra for the same purpose. Tocilizumab was approved by Australia's Therapeutic Goods Administration
Therapeutic Goods Administration
The Therapeutic Goods Administration is the regulatory body for therapeutic goods in Australia . It is a Division of the Australian Department of Health and Ageing established under the Therapeutic Goods Act 1989 ...
on 27 May 2009 and was listed on the Pharmaceutical Benefits Scheme
Pharmaceutical Benefits Scheme
The Pharmaceutical Benefits Scheme or PBS is a program of the Australian Government that provides subsidised prescription drugs to residents of Australia. The PBS ensures that all Australians have affordable and reliable access to a wide range of necessary medicines.-History:The PBS was established...
from 1 August 2010. The FDA approved tocilizumab for the treatment of systemic juvenile idiopathic arthritis for children from two years of age in April 2011, and the EMA followed in August the same year.
Tocilizumab is marketed by Chugai in some countries, especially in Japan and other Asian countries, and jointly by Chugai and Roche (Hoffmann–La Roche's holding company
Holding company
A holding company is a company or firm that owns other companies' outstanding stock. It usually refers to a company which does not produce goods or services itself; rather, its purpose is to own shares of other companies. Holding companies allow the reduction of risk for the owners and can allow...
) in others, for example Great Britain, France and Germany.
Economics
In the UKUnited Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
the drug costs £9,295/year for 70 kg patient for RA treatment. Calculations suggest a base‑case incremental cost-effectiveness ratio
Incremental cost-effectiveness ratio
The incremental cost-effectiveness ratio of an intervention in health care is a term used in cost-effectiveness analysis in health economics. It is defined as the ratio of the change in costs of a therapeutic intervention to the change in effects of the intervention.The term does not...
(ICER) of £19,870 per incremental quality‑adjusted life years (QALYs) for patients with DMARD resistance.