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. |
C (US) |
| Legal status |
℞ Prescription only |
| Routes |
Intravenous infusion |
| 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 Y |
| KEGG |
D02596 Y |
| 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.
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Contents
- 1 Medical uses
- 1.1 Rheumatoid arthritis
- 1.2 Systemic juvenile idiopathic arthritis
- 1.3 Castleman's disease
- 2 Pregnancy and lactation
- 3 Contraindications
- 4 Adverse effects
- 5 Interactions
- 6 Mechanism of action
- 7 History
- 8 Economics
- 9 See also
- 10 References
|
Medical uses
The drug is administered by monthly intravenous infusions. An infusion takes about an hour.[2]
Rheumatoid arthritis
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.[3][4] The drug slows down the progression of the disease and can improve physical function of patients.[5]
Systemic juvenile idiopathic arthritis
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.[6]
Castleman's disease
In Japan, tocilizumab is also approved for the treatment of Castleman's disease,[3][7] a rare benign tumor of B cells.
Pregnancy and lactation
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.[4]
Contraindications
The application of tocilizumab is contraindicated during acute infections, as well as under latent tuberculosis.[8]
Adverse effects
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.[9] 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%).[8]
Interactions
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).[8]
Mechanism of action
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.[8][10]
History
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.[11]
Data presented in 2008 showed the effectiveness of tocilizumab in combination therapy with methotrexate for RA treatment.[12] 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.[13]
In June 2005, tocilizumab was approved in Japan for Castleman's disease.[3] 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.[14] Tocilizumab was approved by Australia's Therapeutic Goods Administration on 27 May 2009[15] and was listed on the Pharmaceutical Benefits Scheme from 1 August 2010.[16] 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.[11]
Economics
In the UK the drug costs £9,295/year for 70 kg patient for RA treatment. Calculations suggest a base‑case incremental cost-effectiveness ratio (ICER) of £19,870 per incremental quality‑adjusted life years (QALYs) for patients with DMARD resistance.[17]
See also
References
- ^ Venkiteshwaran, Adith (2009). "Tocilizumab". MAbs 1 (5): 432–438. doi:10.4161/mabs.1.5.9497. PMC 2759492. PMID 20065633.
- ^ Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.
- ^ 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.
- ^ a b "Assessment report for RoActemra". European Medicines Agency.
- ^ 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
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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
- ^ 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. PMID 19297346.
- ^ a b Markus Harwart (2008). "Die Entwicklung von Tocilizumab" [The development of tocilizumab] (in German). Krankenpflege-Journal.
- ^ BBC News: Jab hope for rheumatoid arthritis
- ^ Oldfield, V; Dhillon, S; Plosker, GL (2009). "Tocilizumab". Drugs 69 (5): 609–632. doi:10.2165/00003495-200969050-00007. PMID 19368420.
- ^ "Roche: FDA Approves Actemra For Rheumatoid Arthritis". The Wall Street Journal. 11 January 2010. [dead link]
- ^ "Australian Drug Evaluation Committee 263rd meeting resolutions". Therapeutic Goods Administration. 27 May 2009.
- ^ "Anakinra (Kineret) to be deleted from the PBS". National Prescribing Service Limited. 1 August 2010.
- ^ "Rheumatoid arthritis - tocilizumab: appraisal consultation document". National Institute for Health and Clinical Excellence.
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Immunomodulators: Immunosuppressive drugs / Immunosuppressants (L04)
|
|
Intracellular
(initiation) |
|
Antimetabolites
|
- purine synthesis inhibitors: Azathioprine
- Mycophenolic acid
- pyrimidine synthesis inhibitors: Leflunomide
- Teriflunomide
antifolate: Methotrexate
|
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Macrolides/
other IL-2 inhibitors
|
- FKBP/Cyclophilin/Calcineurin: Tacrolimus
- Ciclosporin
- Pimecrolimus
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Other
|
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|
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Intracellular
(reception) |
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IL-1 receptor antagonists
|
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|
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mTOR
|
- Sirolimus
- Everolimus
- Ridaforolimus
- Temsirolimus
- Umirolimus
- Zotarolimus
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|
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| Extracellular |
|
Antibodies
|
|
Monoclonal
|
|
Serum target
(noncellular)
|
- Complement component 5 (Eculizumab)
- TNF (Adalimumab
- Afelimomab
- Certolizumab pegol
- Golimumab
- Infliximab
- Nerelimomab)
- Interleukin 5 (Mepolizumab)
- Immunoglobulin E (Omalizumab)
- IL-12 and IL-23 (Lebrikizumab
- Ustekinumab)
|
|
|
Cellular target
|
- CD3 (Muromonab-CD3
- Otelixizumab
- Teplizumab
- Visilizumab)
- CD4 (Clenoliximab
- Keliximab
- Zanolimumab)
- CD11a (Efalizumab)
- CD18 (Erlizumab)
- CD20 (Afutuzumab
- Rituximab
- Ocrelizumab
- Pascolizumab)
- CD23 (Gomiliximab
- Lumiliximab)
- CD40 (Teneliximab
- Toralizumab)
- CD62L/L-selectin (Aselizumab)
- CD80 (Galiximab)
- CD147/Basigin (Gavilimomab)
- CD154 (Ruplizumab)
- BLyS (Belimumab)
- CTLA-4 (Ipilimumab
- Tremelimumab)
- CAT (Bertilimumab
- Lerdelimumab
- Metelimumab)
- Integrin (Natalizumab)
- Interleukin-6 receptor (Tocilizumab)
- LFA-1 (Odulimomab)
- IL-2 receptor/CD25 (Basiliximab
- Daclizumab
- Inolimomab)
- T-lymphocyte (Zolimomab aritox)
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|
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Unsorted
|
- Atorolimumab
- Cedelizumab
- Fontolizumab
- Maslimomab
- Morolimumab
- Pexelizumab
- Reslizumab
- Rovelizumab
- Siplizumab
- Talizumab
- Telimomab aritox
- Vapaliximab
- Vepalimomab
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Polyclonal
|
- Anti-thymocyte globulin
- Anti-lymphocyte globulin
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-cept (Fusion)
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- CTLA-4 (Abatacept
- Belatacept)
- TNF inhibitor (Etanercept
- Pegsunercept)
- Aflibercept
- Alefacept
- Rilonacept
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cell/phys/auag/auab/comp, igrc
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