Identification

Name
Tildrakizumab
Accession Number
DB14004
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

Tildrakizumab is a high-affinity, humanized, IgG1 κ antibody targeting interleukin 23 p19 that shows promise in the evolution of treatment strategy in chronic plaque psoriasis [3].

The Food and Drug Administration (FDA) approved ILUMYA (tildrakizumab-asmn) for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy in March 2018. The approved recommended dosage of ILUMYA is a subcutaneous injection of 100 mg at Weeks 0, 4, and every 12 weeks thereafter [7].

A study was performed on the pharmacokinetics of this drug on various ethnicities. The pharmacokinetics of tildrakizumab were similar in Japanese, Caucasian, and Chinese subjects [5].

Protein chemical formula
C6426H9918N1698O2000S46
Protein average weight
144400.0 Da
Sequences
>Tildrakizumab Sequence
MLGSRAVMLLLLLPWTAQGRAVPGGSSPAWTQCQQLSQKLCTLAWSAHPLVGHMDLREEG
DEETTNDVPHIQCGDGCDPQGLRDNSQFCLQRIHQGLIFYEKLLGSDIFTGEPSLLPDSP
VGQLHASLLGLSQLLQPEGHHWETQQIPSLSPSQPWQRLLLRFKILRSLQAFVAVAARVF
AHGAATLSP
Download FASTA Format
Synonyms
  • tildrakizumab-asmn
External IDs
MK-3222 / SCH 900222
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
IlumyaInjection, solution100 mg/1mLSubcutaneousSun Pharma Global FZE2018-08-06Not applicableUs
Categories
UNII
DEW6X41BEK
CAS number
1326244-10-3

Pharmacology

Indication

Moderate-severe plaque psoriasis [7], [Label].

Pharmacodynamics

Tildrakuzimab is a targeted immunomodulator that decreases inflammation by inhibiting the action of various cytokines associated with plaque psoriasis, thus relieving its symptom of scaly plaques [12], [Label].

Mechanism of action

This drug selectively binds interleukin (IL)-23 p19 subunit of cytokine IL-23 and neutralizes its function IL-23 regulates Th17 cells and is a powerful activator of keratinocyte proliferation [4]. Targeting IL-23p19 alone has been found to be a promising treatment approach in patients with moderate-to-severe chronic plaque psoriasis. Upon administration, downregulation of Th17 and Th22 cell responses occur [3].

IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines [Label].

TargetActionsOrganism
AInterleukin-23
antagonist
Human
Absorption

The mean (± SD) steady-state trough concentrations at 16 weeks post initiation of treatment ranged from 1.22 ± 0.94 mcg/mL to 1.47 ± 1.12 mcg/mL. The geometric mean (CV%) steady-state Cmax was 8.1 mcg/mL (34%) [7].

The absolute bioavailability of tildrakizumab is estimated to be about 73-80% after subcutaneous administration. The peak concentration (Cmax) is reached by approximately 6 days [Label].

Volume of distribution

The geometric mean (CV%) volume of distribution is 10.8 L (24%) [7].

Protein binding
Not Available
Metabolism

The metabolic pathway of tildrakizumab has not been characterized. As a humanized IgG1/k monoclonal antibody, tildrakizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG [7].

The AUCinf of dextromethorphan (CYP2D6 substrate) increased by 20% when used concomitantly with tildrakizumab 200 mg (two times the approved recommended dose) administered subcutaneously at Weeks 0 and 4 in subjects with plaque psoriasis. No clinically significant changes in AUCinf of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) were observed [Label].

Route of elimination
Not Available
Half life

The half-life is approximately 23 days (23%) [7].

Clearance

The mean (CV%) systemic clearance is 0.32 L/day (38%) [7].

Toxicity

It is advised to evaluate patients for tuberculosis infection prior to initiating treatment with ILUMYA. This drug may increase the risk of infection [7]. It is advisable to perform tests for current tuberculosis status, as this drug may lead to reactivation of latent infection [Label].

A common issue for monoclonal antibody drugs is the development of antibodies to the drugs, thus rendering them less effective or completely ineffective [9]. A clinical trial was done to assess antibody development to this drug [7], [Label]. Up until week 64, approximately 6.5% of subjects treated with ILUMYA 100 mg developed antibodies to tildrakizumab. Of the subjects who developed antibodies to tildrakizumab, approximately 40% (2.5% of all patients receiving ILUMYA) had antibodies that were considered neutralizing. The development of neutralizing antibodies to tildrakizumab was associated with lower serum tildrakizumab concentrations and decreased efficacy [Label].

Most common (≥ 1% and at a higher rate than placebo) adverse reactions associated with ILUMYA treatment are upper respiratory infections, injection site reactions, and diarrhea [7].

Cases of angioedema and urticaria occurred in ILUMYA treated subjects in various clinical trials. If a hypersensitivity reaction occurs, the drug should be discontinued immediately and appropriate therapy should be initiated [Label].

In an embryo-fetal study, subcutaneous doses up to 300 mg/kg tildrakizumab were given to pregnant cynomolgus monkeys once every two weeks during organogenesis to 118 days gestation (22 days from parturition). No maternal or embryo-fetal toxicities were seen at doses up to 300 mg/kg (159 times the MRHD of 100 mg, based on AUC comparison). Tildrakizumab crossed the placenta in monkeys [Label].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Tildrakizumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Tildrakizumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Tildrakizumab.
Anthrax immune globulin humanThe therapeutic efficacy of Anthrax immune globulin human can be decreased when used in combination with Tildrakizumab.
Antithymocyte immunoglobulin (rabbit)The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Tildrakizumab.
Bacillus calmette-guerin substrain connaught live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain connaught live antigen can be decreased when used in combination with Tildrakizumab.
Bacillus calmette-guerin substrain tice live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain tice live antigen can be decreased when used in combination with Tildrakizumab.
BasiliximabThe risk or severity of adverse effects can be increased when Basiliximab is combined with Tildrakizumab.
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Tildrakizumab.
BevacizumabThe risk or severity of adverse effects can be increased when Bevacizumab is combined with Tildrakizumab.
Food Interactions
Not Available

References

General References
  1. Papp K, Thaci D, Reich K, Riedl E, Langley RG, Krueger JG, Gottlieb AB, Nakagawa H, Bowman EP, Mehta A, Li Q, Zhou Y, Shames R: Tildrakizumab (MK-3222), an anti-interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo-controlled trial. Br J Dermatol. 2015 Oct;173(4):930-9. doi: 10.1111/bjd.13932. Epub 2015 Oct 15. [PubMed:26042589]
  2. Reich K, Papp KA, Blauvelt A, Tyring SK, Sinclair R, Thaci D, Nograles K, Mehta A, Cichanowitz N, Li Q, Liu K, La Rosa C, Green S, Kimball AB: Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. Lancet. 2017 Jul 15;390(10091):276-288. doi: 10.1016/S0140-6736(17)31279-5. Epub 2017 Jun 6. [PubMed:28596043]
  3. Galluzzo M, D'adamio S, Bianchi L, Talamonti M: Tildrakizumab for treating psoriasis. Expert Opin Biol Ther. 2017 May;17(5):645-657. doi: 10.1080/14712598.2017.1304537. Epub 2017 Mar 17. [PubMed:28271735]
  4. Khalilieh S, Hodsman P, Xu C, Tzontcheva A, Glasgow S, Montgomery D: Pharmacokinetics of Tildrakizumab (MK-3222), an Anti-IL-23 Monoclonal Antibody, Following Intravenous or Subcutaneous Administration in Healthy Subjects. Basic Clin Pharmacol Toxicol. 2018 Mar 6. doi: 10.1111/bcpt.13001. [PubMed:29510001]
  5. Zandvliet A, Glasgow S, Horowitz A, Montgomery D, Marjason J, Mehta A, Xu C, van Vugt M, Khalilieh S: Tildrakizumab, a novel anti-IL-23 monoclonal antibody, is unaffected by ethnic variability in Caucasian, Chinese, and Japanese subjects. Int J Clin Pharmacol Ther. 2015 Feb;53(2):139-46. doi: 10.5414/CP202176. [PubMed:25546162]
  6. Sbidian E, Chaimani A, Garcia-Doval I, Do G, Hua C, Mazaud C, Droitcourt C, Hughes C, Ingram JR, Naldi L, Chosidow O, Le Cleach L: Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis. Cochrane Database Syst Rev. 2017 Dec 22;12:CD011535. doi: 10.1002/14651858.CD011535.pub2. [PubMed:29271481]
  7. FDA Approves ILUMYA (tildrakizumab-asmn) for the Treatment of Adults with Moderate-To-Severe Plaque Psoriasis Who Are Candidates for Systemic Therapy or Phototherapy [Link]
  8. Ilumya [Link]
  9. The safety and side effects of monoclonal antibodies [Link]
  10. The effect of tildrakizumab, a high-affinity, selective anti-IL23p19 monoclonal antibody (mAb), on cytochrome P450 (CYP) metabolism [Link]
  11. Tildrakizumab for treating psoriasis [Link]
  12. Targeted Immunomodulators for the Treatment of Moderate-to-Severe Plaque Psoriasis: Effectiveness and Value [Link]
External Links
KEGG Drug
D10400
Wikipedia
Tildrakizumab
FDA label
Download (535 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentPsoriasis1
2, 3Not Yet RecruitingTreatmentAnkylosing Spondylitis (AS) / Non-radiographic Axial Spondyloarthritis / Psoriatic Arthritis1
3Active Not RecruitingTreatmentPsoriasis Vulgaris (Plaque Psoriasis)2
3WithdrawnTreatmentPsoriasis Vulgaris (Plaque Psoriasis)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous100 mg/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Taxonomy

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

Targets

Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Protein heterodimerization activity
Specific Function
Cytokine that can act as a growth factor for activated T and NK cells, enhance the lytic activity of NK/lymphokine-activated killer cells, and stimulate the production of IFN-gamma by resting PBMC....

Components:
References
  1. Papp K, Thaci D, Reich K, Riedl E, Langley RG, Krueger JG, Gottlieb AB, Nakagawa H, Bowman EP, Mehta A, Li Q, Zhou Y, Shames R: Tildrakizumab (MK-3222), an anti-interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo-controlled trial. Br J Dermatol. 2015 Oct;173(4):930-9. doi: 10.1111/bjd.13932. Epub 2015 Oct 15. [PubMed:26042589]
  2. Ilumya [Link]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Leukotriene-b4 20-monooxygenase activity
Specific Function
Catalyzes the omega- and (omega-1)-hydroxylation of various fatty acids such as laurate, myristate and palmitate. Has little activity toward prostaglandins A1 and E1. Oxidizes arachidonic acid to 2...
Gene Name
CYP4A11
Uniprot ID
Q02928
Uniprot Name
Cytochrome P450 4A11
Molecular Weight
59347.31 Da

Drug created on March 26, 2018 10:38 / Updated on August 02, 2018 07:01