Tocilizumab

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Tocilizumab ?
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Target IL-6 receptor
Clinical data
Trade names Actemra, RoActemra
AHFS/Drugs.com monograph
MedlinePlus a611004
Licence data EMA:Link, US FDA:link
Pregnancy cat.
Legal status
  • Prescription only
Routes Intravenous infusion, subcutaneous injection
Pharmacokinetic data
Half-life 8–14 days during steady state (dependent on concentration)
Identifiers
CAS number 375823-41-9 N
ATC code L04AC07
UNII I031V2H011 YesY
KEGG D02596 YesY
ChEMBL CHEMBL1237022 N
Chemical data
Formula C6428H9976N1720O2018S42 
Mol. mass 145.0 kDa
 N (what is this?)  (verify)

Tocilizumab[1] (INN, or atlizumab, developed by Hoffmann–La Roche and Chugai and sold under the trade names Actemra and RoActemra) is an immunosuppressive drug, mainly for the treatment of rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis, a severe form of RA in children. It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer.

Medical uses[edit]

The drug is administered by monthly intravenous infusions. An infusion takes about an hour.[2] An alternative formulation for subcutaneous injection was approved in October 2013.[3]

Rheumatoid arthritis[edit]

Tocilizumab is used for the treatment of moderate to severe rheumatoid arthritis, applied in combination with methotrexate, if other drugs like disease-modifying antirheumatic drugs (DMARDs) and TNF alpha blockers have proven to be ineffective, or were not tolerated. It can be used as a single medication for patients who do not tolerate methotrexate.[4][5] The drug slows down the progression of the disease and can improve physical function of patients.[6]

Systemic juvenile idiopathic arthritis[edit]

The treatment of systemic juvenile idiopathic arthritis is similar to RA treatment: tocilizumab is combined with methotrexate unless the latter is not tolerated. General safety and effectiveness is established for children of two years and older.[7]

Castleman's disease[edit]

In Japan, tocilizumab is also approved for the treatment of Castleman's disease,[4][8] a rare benign tumor of B cells.

Neuromyelitis optica[edit]

Early case reports suggest tocilizumab might be effective in otherwise refractory neuromyelitis optica (NMO, Devic's disease).[9][10][11][12]

Pregnancy and lactation[edit]

No clinical studies evaluating the risk for unborn children are available. A study using large doses of tocilizumab in pregnant animals has found an increased likelihood for spontaneous abortion and death of the unborn. It is not known whether the drug is secreted into the breast milk, nor if this would pose a risk for the nursling.[5]

Contraindications[edit]

The application of tocilizumab is contraindicated during acute infections, as well as under latent tuberculosis.[13]

Adverse effects[edit]

The most common adverse effects observed in clinical trials were upper respiratory tract infections (more than 10% of patients), nasopharyngitis (common cold), headache, and high blood pressure (at least 5%). The enzyme alanine transaminase was also elevated in at least 5% of patients, but in most cases without symptoms. Elevated total cholesterol levels were common.[14] Among the less common side effects were dizziness, various infections, as well as reactions of the skin and mucosae like mild rashes, gastritis and mouth ulcer. Rare but severe reactions were gastrointestinal perforations (0.26% in six months) and anaphylaxis (0.2%).[13]

Interactions[edit]

There are no certain interactions with other drugs. The blood plasma levels of simvastatin were reduced by 57% after a single dose of tocilizumab, but it is not known whether this is clinically relevant. A possible mechanism is that the elevated IL-6 levels of patients with RA suppress the biosynthesis of various cytochrome P450 enzymes, notably CYP1A2, CYP2C9, CYP2C19 and CYP3A4. Tocilizumab lowers IL-6 and thus normalises cytochrome levels, increasing the metabolization of simvastatin (and possibly other cytochrome metabolised drugs).[13]

Mechanism of action[edit]

Besides other functions, interleukin 6 (IL-6) is involved in the development of immunological and inflammatory reactions. Autoimmune diseases like RA are associated with abnormally high IL-6 levels. Tocilizumab binds soluble as well as membrane bound interleukin-6 receptors, hindering IL-6 from exerting its pro-inflammatory effects.[13][15]

History[edit]

Interleukin 6 and its receptor were discovered and cloned at Osaka University, Japan, by Tadamitsu Kishimoto in the 1980s. In 1997, Chugai Pharmaceuticals began the clinical development of tocilizumab for the treatment of rheumatoid arthritis. Clinical studies for Castleman's disease and systemic juvenile idiopathic arthritis started in 2001 and 2002, respectively. Hoffmann–La Roche co-developed the drug due to a license agreement in 2003.[16]

Data presented in 2008 showed the effectiveness of tocilizumab in combination therapy with methotrexate for RA treatment.[17] In further studies, it was effective and generally well tolerated when administered either as monotherapy or in combination with conventional DMARDs in adult patients with moderate to severe rheumatoid arthritis.[18]

In June 2005, tocilizumab was approved in Japan for Castleman's disease.[4] In January 2009, the drug was approved by the European Medicines Agency (EMA) as RoActemra for the treatment of rheumatoid arthritis under the mentioned restrictions. On 11 January 2010, it was approved by the U.S. Food and Drug Administration (US FDA) as Actemra for the same purpose.[19] Tocilizumab was approved by Australia's Therapeutic Goods Administration on 27 May 2009[20] and was listed on the Pharmaceutical Benefits Scheme from 1 August 2010.[21] The FDA approved tocilizumab for the treatment of systemic juvenile idiopathic arthritis for children from two years of age in April 2011, and the EMA followed in August the same year.

Tocilizumab is marketed by Chugai in some countries, especially in Japan and other Asian countries, and jointly by Chugai and Roche (Hoffmann–La Roche's holding company) in others, for example Great Britain, France and Germany.[16]

See also[edit]

References[edit]

  1. ^ Venkiteshwaran, Adith (2009). "Tocilizumab". MAbs 1 (5): 432–438. doi:10.4161/mabs.1.5.9497. PMC 2759492. PMID 20065633. 
  2. ^ Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X. 
  3. ^ "Genentech Gains FDA Approval for New Subcutaneous Formulation of Actemra for use in Adult Patients Living with Moderately to Severely Active Rheumatoid Arthritis". Genentech. 21 October 2013. 
  4. ^ a b c "RoActemra approved in Europe to treat patients suffering from Rheumatoid Arthritis" (Press release). Hoffmann–La Roche. 2009-01-21. Retrieved 2009-01-05. 
  5. ^ a b "Assessment report for RoActemra". European Medicines Agency. 
  6. ^ Roy Fleischmann et al. (2009). "LITHE: Tocilizumab Inhibits Radiographic Progression and Improves Physical Function in Rheumatoid Arthritis (RA) Patients (Pts) at 2 Yrs with Increasing Clinical Efficacy Over Time". ACR{{inconsistent citations}} 
  7. ^ Chaitow, J; De Benedetti, F; Brunner, H et al. (2010). "Tocilizumab in Patients With Systemic Juvenile Idiopathic Arthritis: Efficacy Data From the Placebo-Controlled 12-Week Part of the Phase 3 TENDER Trial". Ann Rheum Dis 69 (Suppl 3): 146. 
  8. ^ Matsuyama M, Suzuki T, Tsuboi H et al. (2007). "Anti-interleukin-6 receptor antibody (tocilizumab) treatment of multicentric Castleman's disease". Intern. Med. 46 (11): 771–4. doi:10.2169/internalmedicine.46.6262. PMID 17541233. 
  9. ^ Komai T, Shoda H, Yamaguchi K, Sakurai K, Shibuya M, Kubo K, Takahashi T, Fujio K, Yamamoto K (Dec 9, 2013). "Neuromyelitis optica spectrum disorder complicated with Sjogren syndrome successfully treated with tocilizumab: A case report". Mod Rheumatol. 
  10. ^ Kieseier BC, Stüve O, Dehmel T, Goebels N, Leussink VI, Mausberg AK, Ringelstein M, Turowski B, Aktas O, Antoch G, Hartung HP; Stüve; Dehmel; Goebels; Leussink; Mausberg; Ringelstein; Turowski; Aktas; Antoch; Hartung (Mar 1, 2013). "Disease amelioration with tocilizumab in a treatment-resistant patient with neuromyelitis optica: implication for cellular immune responses". JAMA Neurol 70 (3): 390–393. doi:10.1001/jamaneurol.2013.668. PMID 23599943. 
  11. ^ Ayzenberg I, Kleiter I, Schröder A, Hellwig K, Chan A, Yamamura T, Gold R; Kleiter; Schröder; Hellwig; Chan; Yamamura; Gold (Mar 1, 2013). "Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy". JAMA Neurol 70 (3): 394–397. doi:10.1001/jamaneurol.2013.1246. PMID 23358868. 
  12. ^ Araki M, Aranami T, Matsuoka T, Nakamura M, Miyake S, Yamamura T; Aranami; Matsuoka; Nakamura; Miyake; Yamamura (Jul 2013). "Clinical improvement in a patient with neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal antibody tocilizumab". Mod Rheumatol 23 (4): 827–831. doi:10.1007/s10165-012-0715-9. PMC 3713263. PMID 22782533. 
  13. ^ a b c d Dinnendahl, V, Fricke, U, ed. (2010). Arzneistoff-Profile (in German) 4 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3. 
  14. ^ Genovese, M. C.; McKay, J. D.; Nasonov, E. L.; Mysler, E. F.; Da Silva, N. A.; Alecock, E.; Woodworth, T.; Gomez-Reino, J. J. (2008). "Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: The tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study". Arthritis & Rheumatism 58 (10): 2968. doi:10.1002/art.23940. PMID 18821691.  edit
  15. ^ Jones, G; Sebba, A; Gu, J; Lowenstein, MB; Calvo, A; Gomez-Reino, JJ; Siri, DA; Tomsic, M et al. (2010). "Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: The AMBITION study". Annals of the rheumatic diseases 69 (1): 88–96. doi:10.1136/ard.2008.105197. PMC 3747519. PMID 19297346. 
  16. ^ a b Markus Harwart (2008). "Die Entwicklung von Tocilizumab" [The development of tocilizumab] (in German). Krankenpflege-Journal. 
  17. ^ BBC News: Jab hope for rheumatoid arthritis
  18. ^ Oldfield, V; Dhillon, S; Plosker, GL (2009). "Tocilizumab". Drugs 69 (5): 609–632. doi:10.2165/00003495-200969050-00007. PMID 19368420. 
  19. ^ "Roche: FDA Approves Actemra For Rheumatoid Arthritis". The Wall Street Journal. 11 January 2010. [dead link]
  20. ^ "Australian Drug Evaluation Committee 263rd meeting resolutions". Therapeutic Goods Administration. 27 May 2009. 
  21. ^ "Anakinra (Kineret) to be deleted from the PBS". National Prescribing Service Limited. 1 August 2010.