Certolizumab pegol

Identification

Summary

Certolizumab pegol is a tumor necrosis factor (TNF) blocker used to treat a variety of autoimmune and autoinflammatory conditions like Crohn's disease, rheumatoid arthritis, active psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis, and plaque psoriasis.

Brand Names
Cimzia
Generic Name
Certolizumab pegol
DrugBank Accession Number
DB08904
Background

Certolizumab pegol is a pegylated monoclonal antibody against the tumor necrosis factor-alpha (TNF-alpha).1 It is formed with a humanized Fab fragment of 50 kDa, from an IgG 1 isotype, fused to a 40 kDa polyethylene glycol moiety replacing the Fc antibody region. The absence of the Fc region was ideated to prevent complement fixation and antibody-mediated cytotoxicity as well as to markedly increase its half-life.3

Certolizumab does not require glycosylation for active function and hence, its production is significantly more affordable when compared to other existing TNF-alpha therapies as it can be done directly in bacterial hosts such as E. coli.3 It was developed and manufactured by UCB Pharma, first FDA approved in 200811 and updated for a new indication on March 28, 2019.10

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb) / Fusion proteins
Protein Structure
Db08904
Protein Chemical Formula
C2115H3252N556O673S16
Protein Average Weight
91000.0 Da (Pegylated)
Sequences
>Amino acid sequence of the light chain
DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKALIYSASFLYSGVPY
RFSGSGSGTDFTLTISSLQPEDFATYYCQQYNIYPLTFGQGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>Amino acid sequence of the heavy chain
EVQLVESGGGLVQPGGSLRLSCAASGYVFTDYGMNWVRQAPGKGLEWMGWINTYIGEPIY
ADSVKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCARGYRSYAMDYWGQGTLVTVSSAS
TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCAA
References:
  1. Lee JU, Shin W, Son JY, Yoo KY, Heo YS: Molecular Basis for the Neutralization of Tumor Necrosis Factor alpha by Certolizumab Pegol in the Treatment of Inflammatory Autoimmune Diseases. Int J Mol Sci. 2017 Jan 23;18(1). pii: ijms18010228. doi: 10.3390/ijms18010228. [Article]
  2. Patents [Link]
Download FASTA Format
Synonyms
  • Certolizumab pegol
External IDs
  • CDP 870
  • CDP-870
  • CDP870
  • PHA-738144

Pharmacology

Indication

Certolizumab pegol has been approved for several different conditions listed below:

  • Symptomatic management of Chron's disease patients and for the maintenance of clinical response in patients with moderate to severe disease with inadequate response to conventional therapy.
  • Treatment of adult patients with moderate to severely active rheumatoid arthritis.
  • Treatment of adult patients with active psoriatic arthritis.
  • Treatment of adult patients with active ankylosing spondylitis.
  • Treatment of adult patients with moderate-to-severe plaque psoriasis that are candidates for systemic therapy or phototherapy.Label
  • Treatment of adult patients with active non-radiographic axial spondyloarthritis with objective signs of inflammation.10

In Canada, certolizumab pegol is additionally approved in combination with methotrexate for the symptomatic treatment, including major clinical response, and for the reduction of joint damage in adult patients with moderately to severely active rheumatoid arthritis and psoriatic arthritis.12

Inflammation is a biological response against a potential threat. This response can be normal but in certain conditions, the immune system can attack the body's normal cells or tissues which causes an abnormal inflammation.13 TNF-alpha has been identified as a key regulator of the inflammatory response. The signaling cascades of this inflammatory mediator can produce a wide range of reactions including cell death, survival, differentiation, proliferation and migration.7

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

As part of the mechanism of action and nature of the drug, certolizumab does not induce apoptosis in cultured lymphocytes and monocytes. However, as a piece of the inhibition of inflammation, certolizumab pegol inhibits lipopolysaccharide-induced production of IL-1 beta and it induces nonapoptotic cell death via signaling transmembrane TNF-alpha.3

In vitro studies with certolizumab pegol in human tissue did not show any unexpected binding at 3 mcg/ml nor at 10 mcg/ml. Due to the drug class, certolizumab pegol is not expected to present adverse effects on the major vital systems.14

In phase III clinical trials in psoriatic arthritis patients, certolizumab pegol was reported to generate improvements in skin disease, joint involvement, dactylitis, enthesitis and general life quality. The clinical effect of certolizumab was paired to a comparable safety profile to other TNF-alpha inhibitors.3

The clinical effectiveness of certolizumab pegol was mainly studied in six randomized controlled trials that compared its effect versus placebo. In a comparative study, the efficacy for certolizumab pegol registered ranged from 30-65% while in placebo ranged from 4-25%.5 However, in other additional trials, certolizumab was proven to present a similar clinical efficacy to other disease-modifying antirheumatic drugs in patients with inadequate response to TNF inhibitors.2

Mechanism of action

Certolizumab targets the activation of TNF-alpha with high affinity (KD 90 pM and IC90 0.004 mcg/ml) which in order, inhibits the downstream inflammatory process.1 It acts by binding and neutralizing the soluble and membrane portions of TNF-alpha without inducing complement or antibody-dependent cytotoxicity due to the lack of the Fc region. The inhibition of TNF-alpha is achieved in a dose-dependent manner and it does not present activity against lymphotoxin alpha (TNF-beta).3,14

One additional feature od certolizumab pegol is that, due to the presence of the PEGylation, it is more significantly distributed into inflamed tissues when compared to other TNF-alpha inhibitors such as infliximab and adalimumab.3

TargetActionsOrganism
ATumor necrosis factor
neutralizer
Humans
Absorption

After subcutaneous administration, the peak plasma concentration is reached between 54 and 171 hours with a bioavailability of 80%.3 Certolizumab presents a linear pharmacokinetic profile with a peak plasma concentration of 43-49 mcg/ml.14

Volume of distribution

Certolizumab pegol volume of distribution is reported to be in the range of 4-8 L.8 It is known to have a very good distribution in the joints when compared to other TNF-alpha inhibitors.6

Protein binding

Monoclonal antibodies are usually not required to have protein binding studies.

Metabolism

The presence of PEG group in certolizumab pegol delays the metabolism and elimination of this drug. However, once under metabolism, the PEG group gets cleaved from the parent compound and the antibody section is thought to be internalized cells and rescued from metabolism by recycling. Later, it is degraded in the reticuloendothelial system to small peptides and amino acids which can be used for de-novo protein synthesis.4 On the other hand, the PEG section is processed normally by the action of the alcohol dehydrogenase to the formation of carboxylic acid.9

Route of elimination

As certolizumab is a monoclonal antibody, the elimination route is not widely studied. However, it is known that the elimination of the PEG moiety is dependent on the renal function which links it directly with a high portion of renal elimination.3

Half-life

The circulatory half-life of certolizumab is of 14 days.3

Clearance

The clearance rate of certolizumab pegol ranged between 9-14 ml/h when administered intravenously. However, when administered subcutaneously, the clearance rate is estimated to range between 14-21 ml/h depending on the patient condition.14

Adverse Effects
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Toxicity

The oral ld50 observed in mice is determined to be of 300 mg/kg.MSDS To this date, there have not been reports of overdosage, however, in case of accidental overexposure close monitoring is recommended.Label

Certolizumab pegol does not present mutagenic potential nor presents effects in fertility and reproductive performance. On the other hand, carcinogenicity studies have not been performed.Label

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Certolizumab pegol which could result in a higher serum level.
AbataceptThe risk or severity of infection can be increased when Certolizumab pegol is combined with Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be increased when combined with Certolizumab pegol.
AcalabrutinibThe metabolism of Acalabrutinib can be increased when combined with Certolizumab pegol.
AcebutololThe metabolism of Acebutolol can be increased when combined with Certolizumab pegol.
AceclofenacAceclofenac may decrease the excretion rate of Certolizumab pegol which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Certolizumab pegol which could result in a higher serum level.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Certolizumab pegol.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Certolizumab pegol.
AcetazolamideAcetazolamide may increase the excretion rate of Certolizumab pegol which could result in a lower serum level and potentially a reduction in efficacy.
Interactions
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Food Interactions
Not Available

Products

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CimziaSolution200 mgSubcutaneousUcb Inc2017-08-04Not applicableCanada flag
CimziaInjection, solutionSubcutaneousUcb Pharma Sa2020-12-16Not applicableEU flag
CimziaInjection, solutionSubcutaneousUcb Pharma Sa2016-09-08Not applicableEU flag
CimziaInjection, solutionSubcutaneousUcb Pharma Sa2020-12-16Not applicableEU flag
CimziaInjection, solution200 mg/1mLSubcutaneousUCB, Inc.2009-05-14Not applicableUS flag
CimziaInjection, solutionSubcutaneousUcb Pharma Sa2020-12-16Not applicableEU flag
CimziaSolution200 mgSubcutaneousUcb Inc2009-08-31Not applicableCanada flag
CimziaInjection, solutionSubcutaneousUcb Pharma Sa2016-09-08Not applicableEU flag
CimziaInjection, solutionSubcutaneousUcb Pharma Sa2016-09-08Not applicableEU flag
CimziaInjection, solutionSubcutaneousUcb Pharma Sa2020-12-16Not applicableEU flag

Categories

ATC Codes
L04AB05 — Certolizumab pegol
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans

Chemical Identifiers

UNII
UMD07X179E
CAS number
428863-50-7

References

General References
  1. Corbett M, Chehadah F, Biswas M, Moe-Byrne T, Palmer S, Soares M, Walton M, Harden M, Ho P, Woolacott N, Bojke L: Certolizumab pegol and secukinumab for treating active psoriatic arthritis following inadequate response to disease-modifying antirheumatic drugs: a systematic review and economic evaluation. Health Technol Assess. 2017 Oct;21(56):1-326. doi: 10.3310/hta21560. [Article]
  2. Bermejo I, Stevenson M, Archer R, Stevens JW, Goka E, Clowes M, Scott DL, Young A: Certolizumab Pegol for Treating Rheumatoid Arthritis Following Inadequate Response to a TNF-alpha Inhibitor: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. Pharmacoeconomics. 2017 Nov;35(11):1141-1151. doi: 10.1007/s40273-017-0521-5. [Article]
  3. Acosta-Felquer ML, Rosa J, Soriano ER: An evidence-based review of certolizumab pegol in the treatment of active psoriatic arthritis: place in therapy. Open Access Rheumatol. 2016 Mar 30;8:37-44. doi: 10.2147/OARRR.S56837. eCollection 2016. [Article]
  4. Tabrizi MA, Tseng CM, Roskos LK: Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006 Jan;11(1-2):81-8. doi: 10.1016/S1359-6446(05)03638-X. [Article]
  5. D'Angelo S, Tramontano G, Gilio M, Leccese P, Olivieri I: Review of the treatment of psoriatic arthritis with biological agents: choice of drug for initial therapy and switch therapy for non-responders. Open Access Rheumatol. 2017 Mar 2;9:21-28. doi: 10.2147/OARRR.S56073. eCollection 2017. [Article]
  6. Lee JU, Shin W, Son JY, Yoo KY, Heo YS: Molecular Basis for the Neutralization of Tumor Necrosis Factor alpha by Certolizumab Pegol in the Treatment of Inflammatory Autoimmune Diseases. Int J Mol Sci. 2017 Jan 23;18(1). pii: ijms18010228. doi: 10.3390/ijms18010228. [Article]
  7. Bradley JR: TNF-mediated inflammatory disease. J Pathol. 2008 Jan;214(2):149-60. doi: 10.1002/path.2287. [Article]
  8. Vande Casteele N, Mould DR, Coarse J, Hasan I, Gils A, Feagan B, Sandborn WJ: Accounting for Pharmacokinetic Variability of Certolizumab Pegol in Patients with Crohn's Disease. Clin Pharmacokinet. 2017 Dec;56(12):1513-1523. doi: 10.1007/s40262-017-0535-3. [Article]
  9. Webster R, Didier E, Harris P, Siegel N, Stadler J, Tilbury L, Smith D: PEGylated proteins: evaluation of their safety in the absence of definitive metabolism studies. Drug Metab Dispos. 2007 Jan;35(1):9-16. doi: 10.1124/dmd.106.012419. Epub 2006 Oct 4. [Article]
  10. FDA news [Link]
  11. FDA Approved Drug Products: Apadaz (benzhydrocodone and acetaminophen) tablets [Link]
  12. Pubmed books [Link]
  13. Nature [Link]
  14. CIMZIA (Certolizumab) Australian Report [File]
KEGG Drug
D03441
PubChem Substance
347910385
RxNav
709271
ChEMBL
CHEMBL1201831
PharmGKB
PA165107055
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Certolizumab_pegol
AHFS Codes
  • 92:36.00 — Disease-modifying Antirheumatic Agents
  • 56:92.00 — Miscellaneous GI Drugs
FDA label
Download (1.71 MB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentRheumatoid Arthritis2
4CompletedBasic ScienceRheumatoid Arthritis1
4CompletedTreatmentAnterior Uveitis (AU) / Axial Spondyloarthritis (AxSpA)1
4CompletedTreatmentRheumatoid Arthritis7
4RecruitingTreatmentRheumatoid Arthritis1
4TerminatedBasic ScienceRheumatoid Arthritis1
4TerminatedTreatmentCrohn's Disease (CD)1
4TerminatedTreatmentRheumatoid Arthritis1
4Unknown StatusTreatmentAnkylosing Spondylitis (AS) / High Blood Pressure (Hypertension) / Psoriatic Arthritis / Rheumatoid Arthritis1
4Unknown StatusTreatmentCrohn's Disease (CD)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionSubcutaneous200 mg/1mL
Injection, solutionParenteral; Subcutaneous
Injection, solutionSubcutaneous
Injection, solutionSubcutaneous200 mg/1mL
Injection, solutionParenteral
SolutionSubcutaneous200 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2380298No2010-09-282021-06-05Canada flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)61ºCVermeer, A.W.P. & Norde, W., Biophys. J. 78:394-404 (2000)
boiling point (°C)Fab domain denaturates at 60 ºC Arnoldus W. et al. (2000). Biophysical Journal. Vol 78. 394-404
water solubilitySolublePasut G. 2014. BioDrugs.
isoelectric point6.6 - 7.2Jin, et al. Electrophoresis. Sep;23(19):3385-91. (2002).

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Neutralizer
General Function
Tumor necrosis factor receptor binding
Specific Function
Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct ac...
Gene Name
TNF
Uniprot ID
P01375
Uniprot Name
Tumor necrosis factor
Molecular Weight
25644.15 Da
References
  1. 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.S31658. Print 2013. [Article]
  2. Corbett M, Chehadah F, Biswas M, Moe-Byrne T, Palmer S, Soares M, Walton M, Harden M, Ho P, Woolacott N, Bojke L: Certolizumab pegol and secukinumab for treating active psoriatic arthritis following inadequate response to disease-modifying antirheumatic drugs: a systematic review and economic evaluation. Health Technol Assess. 2017 Oct;21(56):1-326. doi: 10.3310/hta21560. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
L-glucuronate reductase activity
Specific Function
Catalyzes the NADPH-dependent reduction of a variety of aromatic and aliphatic aldehydes to their corresponding alcohols. Catalyzes the reduction of mevaldate to mevalonic acid and of glyceraldehyd...
Gene Name
AKR1A1
Uniprot ID
P14550
Uniprot Name
Alcohol dehydrogenase [NADP(+)]
Molecular Weight
36572.71 Da
References
  1. Webster R, Didier E, Harris P, Siegel N, Stadler J, Tilbury L, Smith D: PEGylated proteins: evaluation of their safety in the absence of definitive metabolism studies. Drug Metab Dispos. 2007 Jan;35(1):9-16. doi: 10.1124/dmd.106.012419. Epub 2006 Oct 4. [Article]

Drug created on June 11, 2013 06:11 / Updated on May 11, 2021 01:04