DESCRIPTION
Etanercept (Enbrel®) is a soluble dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR), linked to the Fc portion of human IgG1.
It is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. Treatment of Rheumatoid Arthritis with a Recombinant Human Tumor Necrosis Factor Receptor (p75)–Fc Fusion Protein 1997
CLASSIFICATION
- Immunomodulator: TNF inhibitor.
- Antiarthritic.
INDICATIONS
- Moderate to Severe Rheumatoid Arthritis (RA). Indicated for reducing signs and symptoms, keeping joint damage from getting worse, and improving physical function in patients with moderate to severe rheumatoid arthritis. It can be taken with methotrexate or used alone.
- Moderate to Severe Polyarticular Juvenile Idiopathic Arthritis (JIA). Indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in children ages 2 years and older.
- Psoriatic Arthritis. Indicated for reducing signs and symptoms, keeping joint damage from getting worse, and improving physical function in patients with psoriatic arthritis. It can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.
- Ankylosing Spondylitis (AS) . Indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
- Moderate to Severe Plaque Psoriasis. Indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
Enbrel®
Therapies for Active Rheumatoid Arthritis after Methotrexate Failure 2013
MOLECULAR MECHANISM
Etanercept reduces the effect of naturally present TNF and hence is a TNF inhibitor, functioning as a decoy receptor that binds to TNF.
Tumor necrosis factor-alpha (TNFα) is a cytokine produced by lymphocytes and macrophages. It mediates the immune response by increasing the transport of white blood cells to sites of inflammation, and through additional molecular mechanisms which initiate and amplify inflammation. Elevated levels of TNF are found in involved tissues and fluids of patients with RA, JIA, PsA, AS, and PsO.
Two distinct receptors for TNF (TNFRs), a 55 kDa protein (p55) and a 75 kDa protein (p75), exist naturally as monomeric molecules on cell surfaces and in soluble forms. Biological activity of TNF is dependent upon binding to either TNFR. Etanercept mimics the inhibitory effects of naturally occurring soluble TNF receptors (is a dimeric soluble form of the p75), the difference being that it has a greatly extended half-life in the bloodstream, and therefore a more profound and long-lasting biologic effect than a naturally occurring soluble TNF receptor. It inhibits binding of TNF-α and TNF-β (lymphotoxin alpha) to cell surface TNFRs, rendering TNF biologically inactive.
Etanercept on Wikipedia
Treatment of Rheumatoid Arthritis with a Recombinant Human Tumor Necrosis Factor Receptor (p75)–Fc Fusion Protein 1997
PHARMACOKINETICS
- Absorption: bioavailability following sub-Q administration is approximately 60%. Peak plasma concentrations achieved within 69 hours.
- Distribution: not known whether etanercept crosses the placenta. Not known whether etanercept is distributed into milk.Serum drug levels were determined by a validated ELISA method. After administration of radio-labelled etanercept, nuclear imaging showed distribution of the radioactivity to bone, liver, spleen and kidney, with no delay in clearance from any of these organs.
- Elimination: Half-life 68 hours in healthy adults; 102 hours in adults with rheumatoid arthritis. Enbrel is slowly cleared from the body (t1/2= 70 hours). Clearance was reduced in RA patients (0.066 l/h) compared to healthy volunteers (0.11 l/h). The data collected are consistent with the hypothesis that after binding with TNF, the etanercept-TNF complex is broken down by proteolytic processes in the body in the same way as other proteins; the by-products are either recycled or eliminated via urine or bile.
Measurements of etanercept concentration in synovial fluid (one week before and 4 weeks after treatment) showed a rise in etanercept concentration, suggesting that etanercept penetrates the synovium. After s.c. administration of 25 mg, the maximum plasma concentration was reached after 48 hours. Bioavailability after s.c. adminstration is 76%. The volume of distribution is small (Vss= 10.4 l for a 70 kg subject).
Pharmacokinetics of subcutaneously administered etanercept in subjects with psoriasis 2006
Comparative pharmacokinetics of HD203, a biosimilar of etanercept, with marketed etanercept (Enbrel®): a double-blind, single-dose, crossover study in healthy volunteers 2013
SIDE EFFECTS
- The most common side effects are infections and injection site reactions.
- Serious side effects may include seizures, bruising or bleeding, skin changes (rash, pustules or blistering skin), swelling and difficult breathing or swallowing, vision changes, paresthesias, weakness, and dizziness.
- Hepatitis B can become active if you are a carrier of the hepatitis B virus.
- Blood problems. Symptoms include fever, bruising or bleeding very easily, or looking pale.
- New or worsening heart failure.
- New or worsening psoriasis.
- Allergic reactions.
- Autoimmune reactions, including a lupus-like syndrome and autoimmune hepatitis.
- Risk of cancer. There have been cases of unusual cancers in children and teenage patients who started using TNF-blocking agents at less than 18 years of age. For children, teenagers, and adults taking TNF-blocker medicines, including etanervept, the chances of getting lymphoma or other cancers may increase.People with rheumatoid arthritis or psoriasis, especially those with very active disease, may be more likely to get lymphoma.
- Nervous system problems. Rarely, people who use TNF blocker medicines have developed nervous system problems such as multiple sclerosis, seizures, or inflammation of the nerves of the eyes.
Enbrel®
CONTROINDICATION
DRUG INTERACTION
- Vaccines: most PsA patients receiving etanercept were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccine, but titers in aggregate were moderately lower and fewer patients had 2-fold rises in titers compared to patients not receiving etanercept. The clinical significance of this is unknown. Patients receiving etanercept may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving etanercept.
- Immune-Modulating Biologic Products: combining etanercept with anakinra (Kineret) or abatacept (Orencia), drugs that also reduce the response of the immune system may increase the risk of serious infections.
- Cyclophosphamide: the use of etanercept in patients receiving concurrent cyclophosphamide therapy is not recommended.
- Sulfasalazine: patients in a clinical study who were on established therapy with sulfasalazine, to which etanercept was added, were noted to develop a mild decrease in mean neutrophil counts in comparison to groups treated with either etanercept or sulfasalazine alone.
Enbrel® drug-drug interactions 2012
PHARMACOGENETICS
Pharmacogenetic studies of etanercept have been performed largely in RA. Candidate genes in which polymorphisms have been examined as markers of treatment response to etanercept in RA include: HLA-DRB1 alleles; TNF; lymphotoxin-α (LTA); interleukin-10 (IL10); transforming growth factor β1 (TGFB1); IL-1 receptor antagonist (IL1RN); TNF receptors (TNFRSF1A and TNFRSF1B); and Fc receptors (FCGR2A, FCGR3A and FCGR3B). Of all patients (20%) defined as nonresponders, none of the alleles alone was significantly associated with response to treatment, although particular combinations of alleles in different genes were associated with good or poor responses to etanercept. For example homozygous for both the TNF -308 G and IL10 -1087 G alleles, responded well according to criteria. The combination of alleles in IL1RN (A2 allele corresponding to two copies of an 86-bp repeat in intron 2) and TGFB1 (a rare C allele in codon 25) was associated with a less favorable treatment response. The IL10 promoter microsatellite polymorphisms IL10.R and IL10.G were genotyped, and haplotypes were deduced. A favorable treatment response was associated with the R3 allele or R3–G9 haplotype, whereas the allele G13 and the haplotype R2–G13 were predominant among patients with moderate or poor responses. The presence of two HLA-DRB1 alleles encoding the shared epitope (SE) was associated with response to treatment with etanercept 25 mg twice weekly.
Pharmacogenetics of etanercept in rheumatoid arthritis 2008
DEPENDENCE AND WITHDRAW
Clinical remission and low disease activity are essential treatment targets in patients with rheumatoid arthritis. Although moderately active rheumatoid arthritis is common, treatment effects in moderate disease have not been well studied. Additionally, optimum use of biologics needs further investigation, including the use of induction, maintenance, and withdrawal treatment strategies. The aim of the PRESERVE trial was to assess whether low disease activity would be sustained with reduced doses or withdrawal of etanercept in patients with moderately active disease.Conventional or reduced doses of etanercept with methotrexate in patients with moderately active rheumatoid arthritis more effectively maintain low disease activity than does methotrexate alone after withdrawal of etanercept.
Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial 2013
