Adalimumab

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Adalimumab
Adalimumab
Mass / length primary structure 144.2  kDa
Identifier
External IDs
Drug information
ATC code L04 AB04
DrugBank BTD00049
Drug class Immunosuppressant , monoclonal antibody

Adalimumab is a therapeutic human monoclonal antibody against tumor necrosis factor-α and is therefore also known as a TNF blocker . Adalimumab is used to treat rheumatoid arthritis , psoriatic arthritis , ankylosing spondylitis , uveitis, and inflammatory bowel disease, Crohn's disease and ulcerative colitis .

The originator product Humira , introduced in the USA in 2002 and in the EU in 2003, was the drug with the highest sales worldwide in 2018.

Clinical information

application

Adalimumab is approved in the European Union and Switzerland for the following indications:

for adults to treat

  • moderate to severe rheumatoid arthritis in combination with methotrexate , in case of intolerance to methotrexate also as monotherapy,
  • active and progressive psoriatic arthritis in adults for whom basic therapy has not been successful,
  • severe active ankylosing spondylitis in adults for whom conventional therapy has not been successful,
  • Severe, active Crohn's disease in patients for whom therapy with a glucocorticoid or an immunosuppressant has not been successful,
  • moderate to severe, active ulcerative colitis, in patients who have not responded or not responded adequately to conventional therapy, including glucocorticoids and 6- mercaptopurine or azathioprine ,
  • Plaque-type psoriasis in adults who have not responded to other systemic therapy
  • moderate acne inversa from Hurley stage 2,

for children and adolescents for treatment

  • active polyarticular juvenile idiopathic arthritis in combination with methotrexate (MTX) in children and adolescents aged 4 to 17 years who have had an inadequate response to one or more disease-modifying anti-inflammatory drugs (DMARDs),
  • Severe, active Crohn's disease in children and adolescents (6-17 years old) who have had an inadequate response to, or are intolerant of, conventional therapy, including primary nutritional therapy, a glucocorticoid, and an immunosuppressant such therapy is contraindicated.

Typically, adalimumab is injected subcutaneously every other week in adults . Often the patients do this independently after receiving appropriate instruction. Treatment response should be observed within twelve weeks. In clinical trials, patients were treated with adalimumab for up to five years.

Contraindications and other restrictions on use

Contraindications are hypersensitivity to adalimumab, severe infections such as active tuberculosis , sepsis and opportunistic infections, and heart failure . Infections are so critical because the immune suppressing mechanism of action of adalimumab weakens the body's defense against the infection.

Adalimumab monotherapy increases the likelihood of developing antibodies to adalimumab. This increases clearance and makes adalimumab less effective. Serious infections have been observed with the concomitant use of adalimumab and etanercept with no additional benefit from the combination therapy; therefore this combination is not recommended.

The effects of adalimumab in pregnant women are not known, so it is not recommended during pregnancy. It is also not known whether adalimumab is excreted in breast milk, so breastfeeding should not be carried out during and up to five months after treatment. Adalimumab has not yet been studied in patients with impaired liver or kidney function.

unwanted effects

The most common adverse effects are reactions at the injection site, such as pain, swelling, redness or itching. Headache, muscle and bone pain, nausea and vomiting and rashes, loss of appetite, changes in the blood count (e.g. increase / decrease in white blood cells or anemia ) and increased liver enzyme levels may also occur. Since adalimumab suppresses the immune system, there is an increased risk of developing opportunistic infections , which under certain circumstances can be severe and even lead to sepsis . It can malignant lymphomas occur. Because of this, it is important to carry out close checks (examinations by the dermatologist, gynecologist, etc.).

Pharmacological properties

Mechanism of action

Adalimumab is a human monoclonal antibody of the IgG 1 type that binds highly specifically to the cytokine tumor necrosis factor-alpha (TNF-α) and neutralizes its effect. TNF-α is an important signaling substance of the immune system which, among other things , can trigger the formation of inflammatory mediators in cells . In inflammatory diseases such as rheumatoid arthritis, TNF-α is present in increased concentrations; the neutralization of TNF-α by adalimumab leads to a rapid improvement in various inflammatory parameters such as C-reactive protein and interleukin-6 . In placebo-controlled studies it could be shown that patients after adalimumab treatment showed a significantly improved response according to the criteria of the American College of Rheumatology (ACR). Delayed progression of the disease and an improved quality of life could also be determined. The improvement was determined for up to three years and continued over that period.

Absorption and distribution in the body

The absorption and distribution of adalimumab after a single subcutaneous injection is very slow; the maximum plasma concentration was observed after five days. The absolute bioavailability is 64 percent.

toxicology

No dose limiting toxicity was observed during clinical studies. In animal experiments with rodents, an almost 2000-fold overdose was well tolerated. In experiments with long-tailed macaques , a NOAEL of 32 mg / kg was determined for adalimumab .

Development and marketing

Adalimumab is a recombinant human monoclonal antibody that is produced in CHO cells . The antibody is processed with excipients into an aqueous injection solution with 40 mg adalimumab in 0.4 ml or 0.8 ml solution.

Adalimumab was developed in collaboration between the British biotechnology company Cambridge Antibody Technology (now part of AstraZeneca ) and the pharmaceutical company BASF-Knoll Pharma, now AbbVie . In contrast to many other antibodies, adalimumab was identified from a library of human immunoglobulin sequences by phage display . Adalimumab is therefore a "completely human" antibody. This means that the coding sequences do not contain any cloned elements from other species. However, the structure of the model, IgG1, was heavily modified in vitro to optimize the avidity of the antibody for its target.

The launch of Humira was in December 2002 in the US; approval for the European Union was granted in September 2003. In the year it was launched, Humira was significantly more expensive than other TNF-α blockers such as Enbrel ( Etanercept ) or Remicade ( Infliximab ) and cost many times more than the basic anti-inflammatory drug methotrexate . In 2013, Humira was one of the most commercially successful monoclonal antibodies with annual sales of US $ 10.7 billion. In 2018 Abbvie generated approximately 61% of its net sales with Humira , which corresponds to approximately 19.9 billion US dollars and is considered to be the top-selling drug worldwide. With the market launch of biosimilars there were price reductions for adalimumab.

Adalimumab was also approved in the EU under the brand name Trudexa , but was never marketed under this name. In 2007 Abbott voluntarily abandoned Trudexa for commercial reasons. A number of biosimilars were approved in the EU in 2017 .

Trade names

Humira ( AbbVie Ltd. - EU, USA, CH, CA , JP )

Biosimilars

See also

Web links

literature

  • Jasvinder A. Singh, Robin Christensen, George A. Wells, Maria E. Suarez-Almazor, Rachelle Buchbinder, Maria Angeles Lopez-Olivo, Elizabeth Tanjong Ghogomu, Peter Tugwell: Biologics for rheumatoid arthritis: an overview of Cochrane reviews. In: Cochrane Database of Systematic Reviews. No. 4, 2009, Article No. CD007848, doi: 10.1002 / 14651858.CD007848.pub2 , PMID 19821440 .

Individual evidence

  1. ↑ Humira ® product information, as of February 2013 on the website of the European Medicines Agency (English).
  2. ↑ European Public Assessment Report (EPAR) Humira / Adalimumab (PDF; 97 kB) of the European Medicines Agency (EMA) (German).
  3. ↑ Humira 40 mg / 0.4 ml solution for injection for use in children (PDF; 964 kB), Summary of Product Characteristics (Product Information), as of November 2012.
  4. ↑ New Medicines (PDF; 142 kB) Information from the Medicines Commission of the German Medical Association (AkdÄ) , as of March 19, 2013.
  5. ↑ European Medicines Agency: Initial scientific discussion for the approval of Humira (PDF; 354 ​​kB) .
  6. ↑ A. Vollmar, I. Zündorf, T. Dingermann: Immunology . WVG Stuttgart, 2nd edition, 2013. p. 308
  7. ↑ Adalimumab (Humira) - third TNF-α blocker against rheumatoid arthritis , arznei-telegram at 03/20; 34: 91-2.
  8. ↑ FirstWord Pharma: FirstWord Lists - Biosimilar MAb targets , April 13, 2014.
  9. ↑ AbbVie Annual Report 2018 ("Form K"), p. 2, 13 .
  10. ^ Ev Tebroke: First biosimilars under discount agreement , Pharmazeutische Zeitung, November 8, 2018.
  11. ↑ EMEA / H / C / 482 Trudexa ® (approval withdrawn) , (English, pdf; 33 kB).
  12. ↑ Adalimumab biosimilars introduced in Germany . In: Pro Biosimilars . October 17, 2018 ( probiosimilars.de [accessed November 26, 2018]).