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2010 New Drug Approvals - Pt. I - Tocilizumab (Actemra/RoActemra)




The first FDA approval of this year is Tocilizumab, approved on January 8th, under the trade name Actemra. Tocilizumab is a first-in-class interleukin-6 (IL-6) receptor-inhibiting monoclonal antibody drug, and is indicated for the treatment of rheumatoid arthritis in adults who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. Rheumatoid arthritis is a chronic and debilitating, systematic inflammatory disorder, which affects principally synovial tissues. Tocilizumab ATC code is L04AC07. Tocilizumab works by blocking the signalling of IL-6, an immune system soluble cytokine that is overproduced in patients with rheumatoid arthritis. Other biological therapies for RA include tumor necrosis factor-α (TNF-α) blockers (e.g, Golimumab), IL-1 blockers (e.g., Anakinra), monoclonal antibodies against B cells (e.g., Rituximab) and T cell costimulation inhibitors (e.g., Abatacept). However, all these act through binding to different target molecules. Others drugs with the same IL-6R binding mechanism as Tocilizumab are ALD518 and CNTO-136, which are currently reported to be in Phase II clinical trials. Tocilizumab is a recombinant humanized anti-human IL-6 receptor monoclonal antibody of the immunoglobulin IgG1κ subclass. Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R) - mIL-6R is also known as CD126. Tocilizumab has a molecular weight of ca. 148 kDa, with a volume of distribution of ~6.4L, a linear clearance of ~12.5 mL/h and a half-life up to 13 days. The recommended starting dosage is ~4 mg/kg followed by an increase to ~8 mg/kg based on clinical response, administrated as a single intravenous drip infusion over 1 hour, every 4 weeks. Interestingly, Tocilizumab, via blocking cytokine signalling can affect expression levels of a wide variety of CYP450 drug metabolizing enzymes, leading to the potential for drug-drug interactions. The full prescribing information for Tocilizumab can be found here. Tocilizumab has a boxed warning (Risk of serious infections). Each light and heavy chain of Tocilizumab consists of 214 and 448 amino acids, respectively, and the four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. The license holder of Tocilizumab is Genentech, Inc. and the product website is www.actemra.com.

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