Description
Anakinra was launched in the US as a new daily subcutaneous injection therapy for the
reduction of signs and symptoms of moderately to severely active rheumatoid arthritis (RA)
in adults who have failed to respond to one or more disease-modifying antirheumatic
drugs. Anakinra, N
2-L-methionylinterleukin-1 receptor antagonist (human isoform x
reduced), is the first recombinant non-glycosylated human IL-1 receptor antagonist (IL-lra).
It was isolated from human monocytes, cloned and expressed in Escherichia coll. IL-1ra
is an endogenous cytokine that blocks the binding of the pro-inflammatory cytokine ILl
to its receptor thereby balancing the cartilage destruction and bone resorption mediated
by IL-1. In RA patients, the amount of endogenous IL-lra in the synovial joint is not
sufficient to neutralize the detrimental effects of an excessive level of IL-1. In collageninduced
arthritic mice, continuous i.p. infusion of IL-1ra suppressed the established
arthritis, reduced cartilaginous destruction and restored the synthetic function in articular
cartilage chondrocytes. In clinical trials with RA patients, anakinra was found to attenuate
disease severity and to reduce joint destruction over 6 to 12 months. Treatment with
anakinra was generally well tolerated, although skin reactions at the injection site were
reported. Experiments in rat showed that subcutaneous or intradermal injection of high
doses of anakinra or its vehicle caused a non-immunologically mediated cutaneous mast
cell degranulation.
Originator
Amgen/University of
Colorado (US)
Uses
Anti-inflammatory
(nonsteroidal); suppressant (inflammatory bowel
disease).
Indications
Anakinra (Kineret) is the first antirheumatic agent that
acts by blocking the action of IL-1. This drug was recently
approved for the treatment of moderately to severely
active rheumatoid arthritis in adults who have
not responded to therapy with one or more DMARDs.
Anakinra may be used alone or in combination with
DMARDs other than the TNF antagonists. Clinical
trials have shown anakinra to be more effective
than placebo, either alone or in conjunction with
methotrexate.
brand name
Antril (Synergen);Kineret.
Biological Functions
IL-1Rα plays an
important role for regulating synovial proinflammatory IL-1 activity by preventing IL-1 from binding to IL-1R1. Analysis
of synovial fluid suggests that the rheumatoid synovium is characterized by an overexpression of IL-1. The resulting
imbalance between IL-1 and IL-1Rα has been implicated in perpetuating the pro-inflammatory response and
destructive tide of events in rheumatoid arthritis. If IL-1 is prevented from binding to IL-1R1, the inflammatory
response decreases. The levels of the naturally occurring IL-lRα in synovium and synovial fluid from rheumatoid
arthritis patients are insufficient to compete with the elevated amount of locally produced IL-1.
Pharmacology
Anakinra is a nonglycosylated form of the human IL-1
receptor antagonist (IL-1ra). It is produced in a recombinant
Escherichia coli expression system and has an
additional methionine residue at its amino terminus. In
rheumatoid arthritis patients, the amount of naturally
occurring IL-1ra in the synovial fluid is not sufficient to
counteract the high levels of locally produced IL-1.
Anakinra acts as a competitive antagonist of the type 1
IL-1 receptor and decreases the pain and inflammation
produced by IL-1. It is administered as a daily subcutaneous
injection.
Clinical Use
Anakinra is the first IL-1Rα to be approved for use in adults with moderate to severe active rheumatoid arthritis who
have not responded adequately to conventional DMARD therapy. It may be used either alone or in combination with
methotrexate. Anakinra is supplied in single-use, prefilled, glass syringes as sterile, clear, preservative-free solution
that is administered daily as a self-administered subcutaneous injection under the skin. Some potential side effects
include injection site reactions, decreased white blood cell counts, headache, and an increase in upper respiratory
infections. There may be a slightly higher rate of respiratory infections in people who have asthma or chronic
obstructive pulmonary disease. Persons with an active infection are advised not to use anakinra. Its elimination
half-life after sc administration is 4 to 6 hours.
Side effects
The most common adverse reactions to anakinra are
redness, bruising, pain, and inflammation at the injection
site. Neutropenia may occur, and the risk of serious
infection is somewhat elevated, particularly in asthmatic
patients.Antibodies to anakinra can develop with
long-term therapy, but no correlation between antibody
development and clinical response or adverse effects
has been observed.
Drug interactions
Potentially hazardous interactions with other drugs
Adalimumab, certolizumab, etanercept, golimumab
and infliximab: avoid concomitant use.
Live vaccines: avoid concomitant use.
Metabolism
Renally metabolised and excreted.
Precautions
No drug interaction studies have been conducted in humans.Animal studies indicate no change in the clearanceor toxicity of either methotrexate or anakinrawhen the two agents are administered together. Concomitantadministration of a TNF blocker appears toincrease the risk of serious infection. The response tovaccines may be diminished in patients taking anakinra.
