DB 08904 Certolizumab pegol C 2115 H 3252
DB 08904 Certolizumab pegol C 2115 H 3252 N 556 O 673 S 16 91 k. Da CATEGORY TNF inhibitor
DESCRIPTION Certolizumab pegol is a recombinant Fab’ antibody fragment against tumor necrosis factor alpha which is conjugated to an approximately 40 k. Da polyethylene glycol (PEG 2 MAL 40 K). Polyethylene glycol helps to delay the metabolism and elimination of the drugs. Chemically, the light chain is made up of 214 amino acid residues while the heavy chain is composed of 229 amino acid residues. The molecular mass of the Fab’ antibody fragment itself is 47. 8 k. Da. It is used for the treatment of rheumatoid arthritis and Crohn’s disease. FDA approved on April 22, 2008
INDICATION Reducing signs and symptoms of Crohn's disease and treatment of moderately to severely active rheumatoid arthritis (RA). PHARMACODYNAMICS TNFα is a key pro-inflammatory cytokine with a central role in inflammatory processes. Biological activity associated to TNFα include the upregulation of cellular adhesion molecules and chemokines, upregulation of major histocompatibility complex (MHC) class I and class II molecules, and direct leukocyte activation. TNFα stimulates the production of downstream inflammatory mediators, including interleukin-1, prostaglandins, platelet activating factor, and nitric oxide. After treatment with certolizumab pegol, patients with Crohn's disease demonstrated a decrease in the levels of Creactive protein (CRP).
MECHANISM OF ACTION Certolizumab pegol binds to free and membrane-bound human TNFα with a KD of 90 p. M and neutralizes its activity. Extent of neutralization is also dose-dependent. It also inhibited the release of lipopolysaccharide-induced IL-1β from monocytes. TNFα is a key pro-inflammatory cytokine with a central role in inflammatory processes in which elevated levels have been observed in patients with RA and Crohn's. Certolizumab pegol selectively neutralizes TNFα (IC 90 of 4 ng/m. L for inhibition of human TNFα in the in vitro L 929 murine fibrosarcoma cytotoxicity assay). It does not bind to TNF-β. As certolizumab is only a Fab' fragment and thus missing the Fc region, it does not fix complement or cause antibody-dependent cell-mediated cytotoxicity. Furthermore, apoptosis of monocytes or lymphocytes, or neutrophil degranulation have not been observed in vitro. ABSORPTION There is a linear relationship between dose administered and Cmax and AUC. A mean Cmax of approximately 43 to 49 mcg/m. L occurred at Week 5 during the initial loading dose period using the recommended dose regimen for the treatment of patients with rheumatoid arthritis (400 mg sc at Weeks 0, 2 and 4 followed by 200 mg every other week). Tmax, Sub. Q dose = 54 - 171 hours; Bioavailability, Sub. Q dose = 80% (range of 76% - 88%)
VOLUME OF DISTRIBUTION Vd at steady state in Crohn’s and RA patients = 6 – 8 L ROUTE OF ELIMINATION The route of elimination of certolizumab pegol has not been studied in human subjects. Studies in animals indicate that the major route of elimination of the PEG component is via urinary excretion. HALF LIFE Terminal plasma elimation half-life = 14 days (for all doses); CLEARANCE IV dose, healthy subjects = 9. 21 m. L/h to 14. 38 m. L/h; SC dose, Crohn’s disease patients = 17 m. L/h; SC dose, RA patients = 21. 0 m. L/h; TOXICITY The most common adverse reactions (incidence ≥ 7% and higher than placebo): upper respiratory tract infection, rash, and urinary tract infection.
Cimzia Subcutaneous https: //www. ncbi. nlm. nih. gov/mesh/? term=Certolizumab+pegol TNF blocker. CIMZIA is a recombinant, humanized antibody Fab' fragment, with specificity for human tumor necrosis factor alpha (TNFα), conjugated to an approximately 40 k. Da polyethylene glycol (PEG 2 MAL 40 K). The Fab' fragment is manufactured in E. coli and is subsequently subjected to purification and conjugation to PEG 2 MAL 40 K, to generate certolizumab pegol. The Fab' fragment is composed of a light chain with 214 amino acids and a heavy chain with 229 amino acids. The molecular weight of certolizumab pegol is approximately 91 kilo. Daltons. There have been cases of unusual cancers in children and teenage patients using TNF-blocking agents. CIMZIA is not approved for use in pediatric patients. For people taking TNF-blocker medicines, including CIMZIA, the chances for getting lymphoma or other cancers may increase. People with RA, especially more serious RA, may have a higher chance for getting a kind of cancer called lymphoma
From E. coli, pegylated for longer half-life Recombinant, humanized antibody Fab' fragment, with specificity for human tumor necrosis factor alpha (TNFα). Fab' fragment is manufactured in E. coli and is subsequently subjected to purification and conjugation to PEG 2 MAL 40 K, to generate certolizumab pegol. The Fab' fragment is composed of a light chain with 214 amino acids and a heavy chain with 229 amino acids. The molecular weight of certolizumab pegol is approximately 91 kilo. Daltons FORMULATION Each single-use prefilled syringe of CIMZIA delivers 200 mg in 1 m. L of solution with a p. H of approximately 4. 7 for subcutaneous use. Each 1 m. L syringe of CIMZIA contains certolizumab pegol (200 mg), sodium acetate (1. 36 mg), sodium chloride (7. 31 mg), and Water for Injection, USP. CIMZIA is a clear to opalescent solution that is colorless to pale yellow and essentially free from particulates. No preservatives are present. CLEARANCE: 9. 21 m. L/h to 14. 38 m. L/h HALF-LIFE: 14 days
DOSAGE: Crohn's Disease The recommended initial adult dose of Cimzia is 400 mg (given as two subcutaneous injections of 200 mg) initially, and at Weeks 2 and 4. In patients who obtain a clinical response, the recommended maintenance regimen is 400 mg every four weeks. Rheumatoid Arthritis The recommended dose of Cimzia for adult patients with rheumatoid arthritis is 400 mg (given as two subcutaneous injections of 200 mg) initially and at Weeks 2 and 4, followed by 200 mg every other week. For maintenance dosing, Cimzia 400 mg every 4 weeks can be considered [see Clinical Studies (14. 2)]. Psoriatic Arthritis The recommended dose of Cimzia for adult patients with psoriatic arthritis is 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at week 2 and 4, followed by 200 mg every other week. For maintenance dosing, Cimzia 400 mg every 4 weeks can be considered [see Clinical Studies (14. 3)]. Ankylosing Spondylitis The recommended dose of Cimzia for adult patients with ankylosing spondylitis is 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at weeks 2 and 4, followed by 200 mg every 2 weeks or 400 mg every 4 weeks.
ADVERSE REACTION: Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before CIMZIA use and during therapy. Treatment for latent infection should be initiated prior to CIMZIA use. Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria.
Drug Interactions ABATACEPT Co-administration with other TNF-blocking agents may increase the risk of serious infections. Concomitant therapy is not recommended. ANAKINRA Co-administration with other TNF-blocking agents may increase the risk of serious infections. Concomitant therapy is not recommended. ETANERCEPT Avoid combination as certolizumab pegol toxic effects would be enhanced. GOLIMUMAB Avoid combination due to the potential increased immunosuppression of
INFLIXIMAB Avoid combination because anti-TNF agents increase adverse effects of certolizumab pegol NATALIZUMAB Co-administration with other TNF-blocking agents may increase the risk of serious infections. Concomitant therapy is not recommended. RITUXIMAB Co-administration with other TNF-blocking agents may increase the risk of serious infections. Concomitant therapy is not recommended. TOFACITINIB Certolizumab (and other anti-TNF immunosuppressants), when used in combination with tofacitinib, may increase the risk of added immunosuppression. It is recommended to avoid concurrent therapy.
>Amino acid sequence of the light chain DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKALIYSASFLYSGVPY RFSGSGSGTDFTLTISSLQPEDFATYYCQQYNIYPLTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC >Amino acid sequence of the heavy chain EVQLVESGGGLVQPGGSLRLSCAASGYVFTDYGMNWVRQAPGKGLEWMGWINTYIGEPIY ADSVKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCARGYRSYAMDYWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCAA
REFERENCES • Chimenti MS, Saraceno R, Chiricozzi A, Giunta A, Chimenti S, Perricone R: Profile of certolizumab and its potential in the treatment of psoriatic arthritis. Drug Des Devel Ther. 2013 Apr 15; 7: 339 -48. doi: 10. 2147/DDDT. S 31658. Print 2013. • Ferrante M, Vermeire S, Rutgeerts P: Certolizumab pegol in the treatment of Crohn’s disease. Expert Opin Biol Ther. 2013 Apr; 13(4): 595 -605. doi: 10. 1517/14712598. 2013. 777039. Epub 2013 Mar 4. • https: //data. epo. org/publication-server/rest/v 1. 0/publicationdates/20110803/patents/EP 1534753 NWB 1/document. html • http: //www. ncbi. nlm. nih. gov/pubmed/24662976 • http: //www. ncbi. nlm. nih. gov/pubmed/21047485 • http: //www. ncbi. nlm. nih. gov/pubmed/22915918 • http: //www. ncbi. nlm. nih. gov/pubmed/19155878 • http: //www. ncbi. nlm. nih. gov/pubmed/18927521 • http: //www. ncbi. nlm. nih. gov/pubmed/18474249
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