Infliximab
From Wikipedia, the free encyclopedia
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Infliximab?
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| Therapeutic monoclonal antibody | |
| Source | chimeric/mouse/human |
| Target | TNF |
| Identifiers | |
| CAS number | |
| ATC code | L04 |
| PubChem | ? |
| DrugBank | |
| Chemical data | |
| Formula | C6428H9912N1694O1987S46 |
| Mol. mass | 144190.3 g/mol |
| Pharmacokinetic data | |
| Bioavailability | 100% (IV) |
| Metabolism | reticuloendothelial system |
| Half life | 9.5 days |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
B |
| Legal status | |
| Routes | IV |
Infliximab (Remicade) is a drug used to treat autoimmune diseases.
Infliximab has been approved by the U.S. Food and Drug Administration for the treatment of psoriasis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis and ulcerative colitis. Remicade won its initial approval by the FDA for the treatment of Crohn's disease in August 1998.
Infliximab works by blocking tumour necrosis factor alpha (TNFα). TNFα is a chemical messenger (cytokine) and a key part of the autoimmune reaction. Infliximab blocks the action of TNFα by preventing it from binding to its receptor in the cell.
Inflixmab is an artificial antibody. It was originally developed in mice, as a mouse antibody. Because humans have immune reactions to mouse proteins, it was later developed into a human (humanized) antibody. Because the antibodies were produced from one cell that was grown into a clone of identical cells, it is called a monoclonal antibody. Because it is a combination of mouse and human antibody, it is called a chimeric monoclonal antibody.
Infliximab was developed by Junming Le and Jan Vilcek at New York University School of Medicine and developed by Centocor, a biotechnology company later purchased by Johnson & Johnson.[1]
Infliximab can cost $19,000 to $22,000 a year per patient wholesale, according to Centocor.[2]
Other monoclonal antibodies targeting TNFα are golimumab (Simponi) and adalimumab (Humira.) Etanercept (Enbrel) also binds and inhibits the action of TNFα but is not, strictly speaking, a monoclonal antibody (it is instead a fusion of TNF-receptor and an antibody constant region).
Remicade is administered by intravenous infusion, typically at 6-8 week intervals, and at a clinic or hospital. It cannot be administered orally, because the digestive system would destroy the drug.
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[edit] Pharmacology
According to product labeling, Infliximab neutralizes the biological activity of TNFα by binding with high affinity to the soluble (free floating in the blood) and transmembrane (located on the outer membranes of T cells and similar immune cells) forms of TNFα and inhibits or prevents the effective binding of TNFα with its receptors. Remicade and Humira (another TNF antagonist) are in the subclass of "anti-TNF antibodies" (they are in the form of naturally occurring antibodies), and are capable of neutralizing all forms (extracellular, transmembrane, and receptor-bound) of TNF alpha.[3] Enbrel, a third TNF antagonist, is in a different subclass (receptor-construct fusion protein), and, because of its modified form, cannot neutralize receptor-bound TNFa.[4] Additionally, the anti-TNF antibodies Humira and Remicade have the capability of lysing cells involved in the inflammatory process, whereas the receptor fusion protein apparently lacks this capability.[5] Although the clinical significance of these differences have not been absolutely proven, they may account for the differential actions of these drugs in both efficacy and side effects.
Infliximab has high specificity for TNFα, and does not neutralize TNF beta (TNFβ, also called lymphotoxin α), a related but less inflammatory cytokine that utilizes the same receptors as TNFα. Biological activities that are attributed to TNFα include: induction of proinflammatory cytokines such as interleukin (IL) 1 and IL 6, enhancement of leukocyte movement or migration from the blood vessels into the tissues by increasing the permeability of endothelial layer of blood vessels; and increasing the release of adhesion molecules. Infliximab prevents disease in transgenic mice (a special type of mice that are biologically engineered to produce a human form of TNFα and which are used to test the results of these drugs that might be expected in humans). These experimental mice develop arthritis as a result of their production of human TNFα, and when administered after disease onset, infliximab allows eroded joints to heal.
[edit] Infliximab in Crohn's disease
There are three phenotypes, or categories of disease presentation in Crohn's disease: stricturing disease (which causes narrowing of the bowel), penetrating disease (which causes fistulae or abnormal connections of the bowel), and inflammatory disease (which causes primarily inflammation).[6]
[edit] Fistulizing disease
Infliximab was first used for closure of fistulae in Crohn's disease in 1999. In a 94 patient phase II clinical trial by Present et al., the researchers showed that Infliximab was effective in closing fistulae between the skin and bowel in 56-68% of patients.[7] A large 296 patient Phase III clinical trial conducted by Bruce Sands et al., called the ACCENT 2 trial, showed that infliximab was additionally beneficial in maintaining closure of fistulae, with almost two-thirds of all patients treated with the 3 initial doses REMICADE having a fistula response after 14 weeks, and 36% of patients maintaining closure of fistulae after a year, compared to 19% who received placebo therapy. This final trial resulted in the FDA approval of the drug to treat fistulizing disease.[8], [9]
[edit] Inflammatory disease
Infliximab has also been used in order to induce and maintain remission in inflammatory Crohn's disease. The ACCENT 1 trial was a large multicentre trial that showed that 39 to 45% patients treated with infliximab who had an initial response to it, maintained remission after 30 weeks, compared to 21% who received placebo treatment. It also showed a mean maintenance of remission from 38 to 54 weeks compared to 21 weeks for patients who received placebo treatment.[10]
Crohn's patients have flares of their disease between periods of disease quiescence. Severe flares are usually treated with steroid medications to obtain remission, but steroids have many undesirable side effects, and therefore some gastroenterologists are now advocating for the use of infliximab as the first drug to try to get patients into remission. This has been called the top-down approach to treatment.[11]
[edit] Infliximab in ulcerative colitis
Infliximab targets TNF, thought to be more related to Th1 cytokines. Ulcerative colitis was thought to be a Th2 disease, and Infliximab of limited use. However, patients with ulcerative colitis have begun to be treated with infliximab on the basis of two large clinical trials conducted in 2005 by Paul Rutgeerts and William Sandborn. The ACT 1 and ACT 2 (Acute ulcerative Colitis Treatment) trials evaluated the utility of infliximab in ulcerative colitis and showed that 44-45% of patients treated with infliximab for a year maintained a response to the medication, compared to 21% of patients who were treated with placebo medication. At 2 months, the response was 61-69% for patients treated with infliximab, and 31% for those who were treated with placebo.[12]
[edit] Safety
According to the product labeling of infliximab, etanercept, and adalimumab, these drugs are in the class of immunosuppressants. A number of studies and reports of adverse and serious adverse reactions in patients receiving infliximab have been conducted. Risks include:
- serious and sometimes fatal blood disorders
- serious infections
- lymphoma and solid tissue cancers
- reports of serious liver injury
- reactivation of Hepatitis B
- reactivation of Tuberculosis
- lethal hepatosplenic T-Cell lymphoma
- drug induced lupus
- demyelinating central nervous system disorders
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported with infliximab. [1] The FDA issued a warning to doctors appearing in the respective product labeling of infliximab instructing them to screen and monitor potential patients more carefully [2]. Maintenance therapy with the drug (versus intermittent or sporadic therapy) lessens the likelihood of developing antibodies to infliximab which are known to reduce the efficacy of the drug. Combination treatment with methotrexate (an anti-folate drug which suppresses the immune system) has been shown to reduce the formation of these antibodies in patients with rheumatoid arthritis [13] and combination therapy with other immunosuppressants has been shown to reduce the likelihood of these antibodies being formed in Crohn's disease.[10] The use of immunosuppressants may not be necessary in all diseases for which infliximab is indicated, and indiscriminant use of these other immunosuppressants carry their own risks. Infliximab was studied in monotherapy (without concomitant immunosuppressants such as methotrexate or azathioprine) in psoriasis, psoriatic arthritis, and ankylosing spondylitis. Only its use in rheumatoid arthritis requires the concomitant use of methotrexate by FDA product labeling, however the concomitant use of methotrexate in other disease states may help to reduce the body's immune response to the infliximab and increase its duration of efficacy.
[edit] Other uses
Case studies have been done into other uses of infliximab, such as to treat skin diseases. Remicade (infliximab) has been approved for treating ankylosing spondylitis, Crohn's disease, fistulizing Crohn's disease, pediatric Crohn's disease, psoriatic arthritis, psoriasis, rheumatoid arthritis, and ulcerative colitis. Infliximab is also prescribed (out of indication) for the treatment of Behcet's disease[14] and infusions of infliximab have been used successfully in the treatment of sciatica due to slipped discs.[15]
There have been numerous case reports of the efficacy of infliximab in various inflammatory skin conditions diseases; psoriasis, in which increased TNFα has been demonstrated, is the most recent indication.[16]
Psoriatic arthritis (PsA), a chronic systemic inflammatory disorder characterized by the association of arthritis and psoriasis, follows a heterogeneous and variable clinical course. Inhibitors of TNF, such as infliximab, substantially improve the signs and symptoms of psoriasis (level 1b, grade A). Several therapies with modest efficacy have been studied in nail psoriasis. Among available agents, higher quality data are available to support the efficacy of cyclosporine and infliximab, a TNF antagonist. Based on studies in AS, the results suggest that infliximab, etanercept, and adalimumab have the potential to reduce the signs and symptoms of moderate to severely active axial involvement in PsA in patients who have had an inadequate response to NSAID (level 1a, grade A).The anti-TNF agents (infliximab and etanercept; level 1b, grade A) are more effective for the treatment of enthesitis than traditional agents.Results suggest that infliximab is effective for the treatment of dactylitis in PsA (level 1b, grade B). KAVANAUGH et al., Systematic Review of Treatments for Psoriatic Arthritis: An Evidence Based Approach and Basis for Treatment Guidelines. 2006; J Rheumatol 2006;33:1417–21)
[edit] Availability/Affordability
Like all of the TNF inhibitors, Infliximab is an expensive medication, costing about US$1650 for a 100 mg dose, and is covered by almost every medical insurance plan (though caps on many plans make it possible to be covered for only a subset of treatments in the course of a year).[citation needed]
According to the labeling, the current dosing is:
- Ankylosing Spondylitis: 5 mg per kg
- Crohn's disease: 5 mg per kg
- Psoriatic Arthritis: 5 mg per kg
- Rheumatoid Arthritis: 3 mg per kg
- Psoriasis: 5 mg per kg
[edit] See also
- Adalimumab
- Biological therapy for inflammatory bowel disease
- Etanercept
- Monoclonal antibody
- Tumor necrosis factors
[edit] External links
- National Rheumatoid Arthritis Society (NRAS) Information on anti-TNF drugs such as Infliximab
- Remicade information
- Remicade for Crohn's disease
- Remicade Drug Label
[edit] References
- ^ Knight DM, Trinh H, Le J, Siegel S, Shealy D, McDonough M, Scallon B, Moore MA, Vilcek J, Daddona P, et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol 1993;30:1443-53. PMID 8232330.
- ^ Priced out of pain relief; Insurers balk at high costs of promising new treatments, Victoria Colliver, San Francisco Chronicle, May 8, 2007
- ^ Choy EH et al. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344:907-916
- ^ Etanercept product labeling
- ^ Etanercept, Adalimumab and Infliximab product labeling
- ^ Dubinsky MC, Fleshner PP. (2003). "Treatment of Crohn's Disease of Inflammatory, Stenotic, and Fistulizing Phenotypes". Curr Treat Options Gastroenterol 6 (3): 183–200. doi:. PMID 12744819.
- ^ Present D, Rutgeerts P, Targan S, Hanauer S, Mayer L, van Hogezand R, Podolsky D, Sands B, Braakman T, DeWoody K, Schaible T, van Deventer S (1999). "Infliximab for the treatment of fistulas in patients with Crohn's disease". N Engl J Med 340 (18): 1398–405. doi:. PMID 10228190.
- ^ Sands B, Anderson F, Bernstein C, Chey W, Feagan B, Fedorak R, Kamm M, Korzenik J, Lashner B, Onken J, Rachmilewitz D, Rutgeerts P, Wild G, Wolf D, Marsters P, Travers S, Blank M, van Deventer S (2004). "Infliximab maintenance therapy for fistulizing Crohn's disease". N Engl J Med 350 (9): 876–85. doi:. PMID 14985485.
- ^ www.Remicade.com
- ^ a b Hanauer S, Feagan B, Lichtenstein G, Mayer L, Schreiber S, Colombel J, Rachmilewitz D, Wolf D, Olson A, Bao W, Rutgeerts P (2002). "Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial". Lancet 359 (9317): 1541–9. doi:. PMID 12047962.
- ^ Hanauer S (2003). "Crohn's disease: step up or top down therapy". Best Pract Res Clin Gastroenterol 17 (1): 131–7. doi:. PMID 12617888.
- ^ Rutgeerts P, Sandborn W, Feagan B, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer S, Lichtenstein G, de Villiers W, Present D, Sands B, Colombel J (2005). "Infliximab for induction and maintenance therapy for ulcerative colitis". N Engl J Med 353 (23): 2462–76. doi:. PMID 16339095.
- ^ ATTRACT RA Trial
- ^ Sfikakis PP. Behcet's disease: a new target for anti-tumour necrosis factor treatment. Ann Rheum Dis 2002;61 Suppl 2:ii51-3. PMID 12379622.
- ^ Korhonen T et al. Efficacy fo infliximab for disc herniation-induced sciatica: a one-year follow-up. Spine 2004;29:2115-9.
- ^ Gupta AK, Skinner AR. A review of the use of infliximab to manage cutaneous dermatoses. J Cutan Med Surg 2004;8:77-89. PMID 15685387.
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