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Anakinra
Anakinra is a drug, mostly used to treat rheumatoid arthritis. Additional recommended knowledge
Basic chemical, pharmacological and marketing DataAnakinra is an interleukin-1 (IL-1) receptor antagonist. The anakinra molecule is a recombinant, non glycosolated version of human IL-1RA (RA for receptor antagonist). It consists of 153 amino acids and has a molecular weight of 17,257.6 g/mol (approx. 17.3 kilodaltons) and differs from native human IL-1RA in that it has the addition of a single methionine residue on its amino terminus. The substance is a biologic response modifier. It is prepared from cultures of genetically modified Escherichia coli using recombinant DNA technology. Anakinra blocks the biologic activity of naturally occurring IL-1, including inflammation and cartilage degradation associated with rheumatoid arthritis, by competitively inhibiting the binding of IL-1 to the Interleukin-1 type receptor, which is expressed in many tissues and organs. IL-1 is produced in response to inflammatory stimuli and mediates various physiologic responses, including inflammatory and immunologic reactions. IL-1 additionally stimulates bone resorption and induces tissue damage like cartilage degradation as a result of loss of proteoglycans. In patients with rheumatoid arthritis the natural IL-1 receptor antagonist is not found in effective concentrations in synovium and synovial fluid to counteract the elevated IL-1 concentrations in these patients. Anakinra had an absolute bioavailability of 95% for healthy adults (n = 11) after a 70 mg subcutaneous bolus injection. Peak plasma concentrations of Kineret® generally occurred 3 to 7 hours after s.c. administration of clinically relevant doses (1 to 2 mg/kg: n = 18) for patients with rheumatoid arthritis. The terminal half-life ranged from 4 to 6 hours. After daily s.c. dosing for up to 24 weeks, no unexpected accumulations of Kineret® were observed in the plasma samples of rheumatoid arthritis patients. This drug is sold under the tradename "Kineret®" and is produced by the pharmaceutical company Amgen. It is delivered as injection concentrate containing 100mg each single dose. IndicationsAnakinra is indicated as monotherapeutic agent or in combination with other disease-modifying agents (DMARDs) other than tumor necrosis factor α (TNF-α) blocking agents for the management of signs and symptoms of rheumatoid arthritis and to inhibit the progression of structural damage associated with the disease in adults with moderately to severely active disease who have had an absence of clinical improvement of symptoms or inadequate response in therapy with one or more DMARDs. Anakinra should not be used in combination with etanercept (Enbrel®) or infliximab (Remicade®). Kineret® showed moderate but statistically significant therapeutic efficacy; in most studies methotrexate was administered concomitantly. In the methotrexate plus anakinra group 38% of 250 patients reached an improvement/relief of symptoms of at least 20% within 24 weeks. In the control group of 251 patients under methotrexate treatment alone response was seen in 22% only. The clinical response was measured according to ACR-criteria (20, 50, and 70). There are no direct studies comparing anakinra with TNF-α inhibitors, but indirect data suggests that anakinra may be inferior to TNF-α inhibitors. In a study with infliximab plus methotrexate 50% of all patients had significant remission (according to at least ACR 20 criteria) after a 30-week treatment period. Contraindications and precautions
Precautions:
Side-effects
Recommended Laboratory TestsIn patients receiving Kineret® a decrease in neutrophil counts may be found. In the placebo-controlled studies 8% of patients receiving anakinra had decreases in neutrophil counts of at least 1 World Health Organization (WHO) toxicity grade compared with 2% in the placebo control group. Kineret®-treated patients experienced defined neutropenia (ANC < 1 x 109/L) in 0.4%. Neutrophil counts should be assessed prior to initiating Kineret® treatment, and while receiving Kineret®, monthly for 3 months, and thereafter quarterly for a period up to 1 year. MalignanciesAmong 5,300 rheumatoid arthritis patients treated with Kineret® in clinical trials for a mean of 15 months (approximately 6,400 patient years of treatment), 8 cases of lymphomas were observed resulting in a rate of 0.12 cases/100 patient years. This is 3.6 fold higher than the rate of lymphomas expected in the general population. However, it should be noted that the 'natural' incidence of lymphomas in patients with rheumatoid arthritis is considerably increased and may even be higher in patients with high disease activity. Additionally, 37 solid tumors of different origination have been found. Of these, the number of 3 melanomas reported in study 4 is significant (1 case expected), but the clear association to anakinra therapy remains unclear. At this stage it cannot be ruled out that anakinra is a human carcinogen. Interactions
An increased incidence of serious infections and an increased risk of neutropenia have been seen when anakinra and etanercept were used concomitantly in patients with rheumatoid arthritis. Similar interactions can be anticipated for the combination therapy of anakinra together with other agents blocking TNF (alpha) (e.g., adalimumab, infliximab). Therefore, combined drug therapy with anakinra and any TNF-blocking agent is not recommended and should be avoided. Moreover, in a 24-week clinical study a regime with anakinra and etanercept did not provide any additional benefit to the patients.
Methotrexate has been coadministered with anakinra in quite extended clinical studies. Neither specific drug interactions nor increased toxicity of anakinra and/or methotrexate have been noticed. In animal models (rats) studying the effects of both drugs when coadminstered, no effects on clearing of both drugs form plasma or on the respective toxicologic properties have been seen. Therefore, the concomitant use of both disease modifiers in patients with rheumatoid arthritis can be regarded as safe.
Live-virus vaccines should not be given to patients during anakinra treatment. Information is not available, if anakinra would affect the rate of secondary transmission of vaccine virus (e.g., measles or poliomyelitis viruses) following administration of a live virus vaccine or regarding any other effect of vaccination on patients receiving the drug. Due to the fact that anakinra decreases the immune response to antigens in general, vaccine efficacy may be reduced in patients receiving anakinra. Dosage regimeThe usual dosage is 100mg subcutaneosly (s.c.) once a day. Dose reduction to 100mg s.c. every other day should be considered in patients with severe renal impairment, if these are treated in exceptional cases (see contraindications and precautions). No additional benefits of doses exceeding 100mg daily have been seen. Duration of treatmentIn the pre-clinical and clinical studies the usual duration of therapy was 24 weeks. It is possible to extend therapy to 48 weeks in patients with satisfying remission after 24 weeks to maintain clinically evident improvements. Under continued therapy anakinra has been shown to slow progression of disease over a period of at least 12 month evidenced by X-ray studies or other clinical examinations. Some experience with 48 to 60 weeks (15 months) treatment duration has already been gained and no evidence has been seen regarding additional toxicity. Possible future indicationsDue to the specific mechanism of action of anakinra, a possible efficiency may be anticipated in patients with inflammatory joint diseases such as psoriatic arthritis, and spondylarthritis. Possibly, anakinra may even benefit patients with destructive osteoarthritis in inflammatory phases. Kineret® may also be effective in pediatric patients with juvenile rheumatoid arthritis (JRA). Clinical studies have not been initiated so far regarding these diseases. Currently, the use of anakinra in these patients is therefore not recommended. On April 12, 2007 an article in the New England Journal of Medicine discussed the possibility of using anakinra for treatment of type 2 diabetes. References and external links
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This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Anakinra". A list of authors is available in Wikipedia. |