1. Certolizumab pegol DB08904 C2115H3252N556O673S16 91 kDa CATEGORY
TNF inhibitor

2. DESCRIPTION
Certolizumab pegol is a recombinant Fab’ antibody fragment against tumor necrosis factor alpha which is conjugated to an approximately 40kDa polyethylene glycol (PEG2MAL40K). 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 kDa. It is used for the treatment of rheumatoid arthritis and Crohn’s disease. FDA approved on April 22, 2008

3. 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 C-reactive protein (CRP).

4. MECHANISM OF ACTION
Certolizumab pegol binds to free and membrane-bound human TNFα with a KD of 90pM 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 (IC90 of 4 ng/mL for inhibition of human TNFα in the in vitro L929 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/mL 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, SubQ dose = hours; Bioavailability, SubQ dose = 80% (range of 76% - 88%)

5. 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 mL/h to mL/h;
SC dose, Crohn’s disease patients = 17 mL/h;
SC dose, RA patients = 21.0 mL/h;
TOXICITY
The most common adverse reactions (incidence ≥7% and higher than placebo): upper respiratory tract infection, rash, and urinary tract infection.

6. Cimzia Subcutaneous
TNF blocker. CIMZIA is a recombinant, humanized antibody Fab' fragment, with specificity for human tumor necrosis factor alpha (TNFα), conjugated to an approximately 40kDa polyethylene glycol (PEG2MAL40K). The Fab' fragment is manufactured in E. coli and is subsequently subjected to purification and conjugation to PEG2MAL40K, 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 kiloDaltons. 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

7. 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 PEG2MAL40K, 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 kiloDaltons
FORMULATION
Each single-use prefilled syringe of CIMZIA delivers 200 mg in 1 mL of solution with a pH of approximately 4.7 for subcutaneous use. Each 1 mL 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 mL/h to mL/h
HALF-LIFE: 14 days

8. 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.

9. 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.

10. Drug Interactions ABATACEPT Co-administration with other TNF-blocking agents may increase the risk of serious infections. Concomitant therapy is not recommended. ANAKINRA ETANERCEPT Avoid combination as certolizumab pegol toxic effects would be enhanced. GOLIMUMAB Avoid combination due to the potential increased immunosuppression of

11. 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
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.

12. >Amino acid sequence of the light chain
DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKALIYSASFLYSGVPY
RFSGSGSGTDFTLTISSLQPEDFATYYCQQYNIYPLTFGQGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>Amino acid sequence of the heavy chain
EVQLVESGGGLVQPGGSLRLSCAASGYVFTDYGMNWVRQAPGKGLEWMGWINTYIGEPIY
ADSVKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCARGYRSYAMDYWGQGTLVTVSSAS
TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCAA

13. 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 Apr 15;7: doi: /DDDT.S Print 2013.
Ferrante M, Vermeire S, Rutgeerts P: Certolizumab pegol in the treatment of Crohn’s disease. Expert Opin Biol Ther Apr;13(4): doi: / Epub 2013 Mar 4.