Abrocitinib

Identification

Summary

Abrocitinib is a kinase inhibitor used to treat moderate-to-severe atopic dermatitis in adults.

Generic Name

Abrocitinib

DrugBank Accession Number

DB14973

Background

Abrocitinib is an oral small-molecule inhibitor of Janus kinase 1 (JAK1). Janus kinases are intracellular enzymes involved in transduction pathways that regulate hematopoiesis and immune cell function.⁶ The Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling pathway plays a central role in the pathogenesis of a variety of autoimmune and inflammatory diseases, including atopic dermatitis, a chronic inflammatory skin disease with complex pathogenesis. Atopic dermatitis is characterized by epidermal hyperplasia, skin barrier dysfunction, and the aberrant activation of immune cells. Patients with moderate-to-severe atopic dermatitis report reduced quality of life and often face limited treatment options. JAK inhibitors recently attracted more attention as potential treatments for inflammatory disorders, as JAK inhibition is associated with rapid and sustained anti-inflammatory efects.²

Abrocitinib was approved by the European Commission on December 10, 2021, for the treatment of moderate-to-severe atopic dermatitis (AD) in adults who are candidates for systemic therapy.⁸ On January 14, 2022, the FDA approved abrocitinib for the treatment of refractory, moderate-to-severe AD in adults whose disease is not adequately controlled with other systemic drug products, including biologics, or when the use of those therapies is inadvisable.⁷ Health Canada also approved the use of abrocitinib in pediatric patients 12 years and older.⁹

Type

Small Molecule

Groups

Approved, Investigational

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Abrocitinib (DB14973)

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Weight

Average: 323.42
Monoisotopic: 323.14159611

Chemical Formula

C₁₄H₂₁N₅O₂S

Synonyms

• Abrocitinib
• PF-04965842

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Pharmacology

Indication

Abrocitinib is indicated for the treatment of moderate-to-severe atopic dermatitis in adults who are candidates for systemic therapy.⁶ In the US, it is indicated to treat refractory, moderate-to-severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when the use of those therapies is inadvisable.⁵

Abrocitinib is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants.⁵

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Management of	Severe atopic dermatitis		••••••••••••	•••••	••••••••• ••• •••••••• •••••••	••••••
Management of	Moderate atopic dermatitis		••••••••••••	•••••	••••••••• ••• •••••••• •••••••	••••••
Management of	Moderate, refractory atopic dermatitis		••••••••••••	•••••• •••••••••	•••••••••• •• •• •••••••••• •• ••••• •••••••••• ••••••• •• •• ••••• ••• ••••• •••••••• •••••••	••••••
Management of	Moderate, refractory atopic dermatitis		••••••••••••		•••••••••• •• •• •••••••••• •• ••••• •••••••••• ••••••• •• •• ••••• ••• ••••• •••••••• •••••••	••••••
Management of	Refractory, severe atopic dermatitis		••••••••••••	•••••• •••••••••	••••••• •• •• ••••• ••• ••••• •••••••• •••••••• •••••••••• •• •• •••••••••• •• ••••• •••••••••	••••••

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Pharmacodynamics

Abrocitinib mediates anti-inflammatory effects by blocking the signalling of pro-inflammatory cytokines implicated in atopic dermatitis.⁴ It dose-dependently reduces the serum markers of inflammation in atopic dermatitis, including high sensitivity C-reactive protein (hsCRP), interleukin-31 (IL-31), and thymus and activation regulated chemokine (TARC). These changes returned to near baseline within four weeks following drug discontinuation.⁵ At two weeks of treatment, the mean absolute lymphocyte count increased, which returned to baseline by nine months of treatment. Treatment with abrocitinib was associated with a dose-related increase in B cell counts and a dose-related decrease in NK cell counts: the clinical significance of these changes is unknown.⁶

Treatment with 200 mg abrocitinib once-daily was associated with a transient, dose-dependent decrease in platelet count with the nadir occurring at a median of 24 days. Recovery of platelet count (~40% recovery by 12 weeks) occurred without discontinuation of the treatment.⁵

Mechanism of action

Janus kinases (JAKs) are a family consisting of four receptor-associated kinases - JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Upon ligand binding and subsequent dimerization of cytokine and hormone receptors, receptor-associated JAKs are activated and phosphorylated. This allows the binding of Signal Transducers and Activators of Transcription (STATs), which are transcription factors. STAT binds to the receptor, and JAK phosphorylates and activates STAT to create a STAT dimer. The STAT dimer translocates to the nucleus to upregulate the gene transcription of pro-inflammatory cytokines and growth factors implicated in atopic dermatitis.^3,2 Blocking the JAK-STAT pathway is advantageous, as it is an intracellular signalling pathway where many pro-inflammatory pathways converge.⁴

Each JAK plays a role in the signalling and regulation of different cytokines and immune cells. In atopic dermatitis, JAK1 is the therapeutic target of focus as it is involved in the signalling of the γc family of cytokines involved in immune responses and disease pathophysiology, including IL-2, IL-4, IL-7, IL-9, and IL-15.² Abrocitinib reversibly inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site. Biochemical assays demonstrate that abrocitinib is selective for JAK1 over JAK2 (28-fold), JAK3 (>340-fold), and tyrosine kinase (TYK) 2 (43-fold), as well as the broader kinome.⁵ Similarly, in cellular settings, abrocitinib preferentially inhibited cytokine-induced STAT phosphorylation by signalling pairs involving JAK1, while sparing signalling by JAK2/JAK2, or JAK2/TYK2 pairs.⁶ The relevance of inhibition of specific JAK enzymes to the drug's therapeutic effectiveness is currently unknown.⁵

Target	Actions	Organism
ATyrosine-protein kinase JAK1	inhibitor	Humans
UTyrosine-protein kinase JAK2	inhibitor	Humans
UTyrosine-protein kinase JAK3	inhibitor	Humans
UNon-receptor tyrosine-protein kinase TYK2	inhibitor	Humans

Absorption

Abrocitinib is absorbed with over 91% extent of oral absorption and absolute oral bioavailability of approximately 60%. The peak plasma concentrations of abrocitinib are reached within one hour. Steady-state plasma concentrations of abrocitinib are achieved within 48 hours after once-daily administration. Both C_max and AUC of abrocitinib increased dose proportionally up to 200 mg.⁵

A high-fat meal, high-calorie meal increased AUC by 26% and C_max by 29%, and prolongs T_max by two hours; however, there are ultimately no clinically relevant effect on abrocitinib exposures.⁵

Volume of distribution

After intravenous administration, the volume of distribution of abrocitinib was approximately 100 L.⁵

Protein binding

Approximately 64%, 37% and 29% of circulating abrocitinib and its active metabolites M1 and M2, respectively, are bound to plasma proteins. Abrocitinib and its active metabolites M1 and M2 bind predominantly to albumin and distribute equally between red blood cells and plasma.⁵

Metabolism

Abrocitinib undergoes CYP-mediated oxidative metabolism. CYP2C19 is the predominant enzyme, accounting for about 53% of drug metabolism. CYP2C9 is responsible for 30% of drug metabolism. About 11% and 6% of the drug is metabolized by CYP3A4 and CYP2B6, respectively. In a human radiolabeled study, the parent drug was the most prevalent circulating species. Polar mono-hydroxylated metabolites of abrocitinib - M1 (3-hydroxypropyl; PF-06471658), M2 (2-hydroxypropyl; PF-07055087), and M4 (pyrrolidinone pyrimidine; PF-07054874) - were also identified in the systemic circulation.^5,6 M2 has a chiral center, thus has an enantiomer M3 (PF-07055090).¹ At steady state, M2 and M4 are major metabolites and M1 is a minor metabolite.⁶

M2 has a pharmacological activity comparable to abrocitinib while M1 is less pharmacologically active than abrocitinib. M3 and M4 are inactive metabolites. The pharmacologic activity of abrocitinib is attributable to the unbound exposures of the parent molecule (~60%) as well as M1 (~10%) and M2 (~30%) in the systemic circulation. The sum of unbound exposures of abrocitinib, M1 and M2, each expressed in molar units and adjusted for relative potencies, is referred to as the abrocitinib active moiety.⁶

Hover over products below to view reaction partners

• Abrocitinib
  • Abrocitinib M2 metabolite
  • Abrocitinib M3 metabolite
  • Abrocitinib M4 metabolite
  • Abrocitinib M1 metabolite

Route of elimination

Abrocitinib is eliminated primarily by metabolic clearance mechanisms, with less than 1% of the dose being excreted in urine as an unchanged parent drug. The metabolites of abrocitinib are excreted predominantly in urine.⁵

Pharmacokinetics data up to and including a single oral dose of 800 mg in healthy adult volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 48 hours.⁶

Half-life

The mean elimination half-lives of abrocitinib and its two active metabolites, M1 and M2, range from three to five hours.⁵

Clearance

There is no information available.

Adverse Effects

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Toxicity

There is no experience regarding human overdosage with abrocitinib.⁵ In clinical trials, there were no specific toxicities observed when abrocitinib was administered in single oral doses of 800 mg and 400 mg daily for 28 days. An overdose should be responded with symptomatic and supportive treatment, as there is no specific antidote for overdose with abrocitinib.⁶

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abatacept	The metabolism of Abrocitinib can be increased when combined with Abatacept.
Abciximab	The risk or severity of bleeding and thrombocytopenia can be increased when Abciximab is combined with Abrocitinib.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Abrocitinib.
Acenocoumarol	The metabolism of Abrocitinib can be decreased when combined with Acenocoumarol.
Acetohexamide	The metabolism of Abrocitinib can be decreased when combined with Acetohexamide.

Food Interactions

• Take at the same time every day. Administer with or without food, as it has no clinically relevant effect on abrocitinib exposures.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Cibinqo	Tablet, film coated	50 mg/1	Oral	U.S. Pharmaceuticals	2022-02-24	Not applicable
Cibinqo	Tablet, film coated	200 mg/1	Oral	Pfizer Laboratories Div Pfizer Inc	2022-02-24	Not applicable
Cibinqo	Tablet, film coated	200 mg	Oral	Pfizer Europe Ma Eeig	2022-01-20	Not applicable
Cibinqo	Tablet, film coated	200 mg	Oral	Pfizer Europe Ma Eeig	2022-01-20	Not applicable
Cibinqo	Tablet, film coated	100 mg	Oral	Pfizer Europe Ma Eeig	2022-01-20	Not applicable

Categories

ATC Codes

D11AH08 — Abrocitinib

• D11AH — Agents for dermatitis, excluding corticosteroids
• D11A — OTHER DERMATOLOGICAL PREPARATIONS
• D11 — OTHER DERMATOLOGICAL PREPARATIONS
• D — DERMATOLOGICALS

Drug Categories

• Agents for Dermatitis, Excluding Corticosteroids
• Amides
• Cytochrome P-450 CYP2B6 Substrates
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Dermatologicals
• Enzyme Inhibitors
• Janus Kinase 1, antagonists & inhibitors
• Janus Kinase Inhibitor
• Janus Kinase Inhibitors
• Janus Kinases, antagonists & inhibitors
• OAT3/SLC22A8 Substrates
• OCT1 inhibitors
• P-glycoprotein inhibitors
• Protein Kinase Inhibitors
• Sulfones
• Sulfur Compounds

Classification

Not classified

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

73SM5SF3OR

CAS number

1622902-68-4

InChI Key

IUEWXNHSKRWHDY-PHIMTYICSA-N

InChI

InChI=1S/C14H21N5O2S/c1-3-6-22(20,21)18-10-7-11(8-10)19(2)14-12-4-5-15-13(12)16-9-17-14/h4-5,9-11,18H,3,6-8H2,1-2H3,(H,15,16,17)/t10-,11+

IUPAC Name

N-[(1s,3s)-3-[methyl({7H-pyrrolo[2,3-d]pyrimidin-4-yl})amino]cyclobutyl]propane-1-sulfonamide

SMILES

CCCS(=O)(=O)N[C@H]1C[C@H](C1)N(C)C1=C2C=CNC2=NC=N1

References

General References

1. Tripathy S, Wentzel D, Wan XK, Kavetska O: Validation of enantioseparation and quantitation of an active metabolite of abrocitinib in human plasma. Bioanalysis. 2021 Oct;13(19):1477-1486. doi: 10.4155/bio-2021-0128. Epub 2021 Oct 4. [Article]
2. He H, Guttman-Yassky E: JAK Inhibitors for Atopic Dermatitis: An Update. Am J Clin Dermatol. 2019 Apr;20(2):181-192. doi: 10.1007/s40257-018-0413-2. [Article]
3. Roskoski R Jr: Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res. 2016 Sep;111:784-803. doi: 10.1016/j.phrs.2016.07.038. Epub 2016 Jul 26. [Article]
4. Crowley EL, Nezamololama N, Papp K, Gooderham MJ: Abrocitinib for the treatment of atopic dermatitis. Expert Rev Clin Immunol. 2020 Oct;16(10):955-962. doi: 10.1080/1744666X.2021.1828068. Epub 2020 Oct 8. [Article]
5. FDA Approved Drug Products: CIBINQO (abrocitinib) tablets, for oral use [Link]
6. Summary of Product Characteristics: Cibinqo (abrocitinib) oral tablets [Link]
7. Pfizer News: U.S. FDA Approves Pfizer’s CIBINQO® (abrocitinib) for Adults with Moderate-to-Severe Atopic Dermatitis [Link]
8. Pfizer News: European Commission Approves Pfizer’s Cibinqo® (abrocitinib) for the Treatment of Adults with Moderate-to-Severe Atopic Dermatitis [Link]
9. Health Canada Approved Drug Products: CIBINQO (abrocitinib) tablets, for oral use [Link]
10. FDA Approved Drug Products: CIBINQO™ (abrocitinib) tablets, for oral use (February 2023) [Link]

External Links

ChemSpider

58824300

BindingDB

159748

RxNav

2591476

ChEMBL

CHEMBL3655081

PDBe Ligand

D7D

Wikipedia

Abrocitinib

PDB Entries

6bbu / 6bbv

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Recruiting	Treatment	Atopic Dermatitis	1
3	Active Not Recruiting	Treatment	Atopic Dermatitis	2
3	Completed	Treatment	Allergic Reaction / Atopic Dermatitis / Dermatitis / Genetic Diseases, Inborn / Immune System Diseases / Skin Diseases / Skin Diseases, Eczematous / Skin Diseases, Genetic / Type I Hypersensitivity	2
3	Completed	Treatment	Atopic Dermatitis	4
2	Completed	Treatment	Atopic Dermatitis	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	100 mg
Tablet	Oral	200 mg
Tablet	Oral	50 mg
Tablet, film coated	Oral	100 mg/1
Tablet, film coated	Oral	200 mg/1
Tablet, film coated	Oral	50 mg/1
Tablet, film coated	Oral	100 mg
Tablet, film coated	Oral	200 mg
Tablet, film coated	Oral	50 mg
Tablet, coated	Oral	100 mg
Tablet, coated	Oral	200 mg
Tablet, coated	Oral	50 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9549929	No	2017-01-24	2034-02-19
US9545405	No	2017-01-17	2034-02-19
US9035074	No	2015-05-19	2034-02-19

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.42 mg/mL	ALOGPS
logP	0.93	ALOGPS
logP	0.83	Chemaxon
logS	-2.9	ALOGPS
pKa (Strongest Acidic)	11.47	Chemaxon
pKa (Strongest Basic)	6.45	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	5	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	90.98 Å2	Chemaxon
Rotatable Bond Count	5	Chemaxon
Refractivity	86 m3·mol-1	Chemaxon
Polarizability	34.18 Å3	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00di-0009000000-0a54c6f121552c203d4a
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00di-0009000000-0c30d9128fd90fa390ef
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0udj-0590000000-e4b2d771e2d29ea6a1ca
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0002-0911000000-2cbd9b55d83453540100
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00fs-9717000000-a6f062cbc6fe73ced476
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0002-1910000000-792748620245a6522be5
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Details1. Tyrosine-protein kinase JAK1

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Ubiquitin protein ligase binding

Specific Function

Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor.

Gene Name

JAK1

Uniprot ID

P23458

Uniprot Name

Tyrosine-protein kinase JAK1

Molecular Weight

133275.995 Da

References

1. FDA Approved Drug Products: CIBINQO (abrocitinib) tablets, for oral use [Link]

Details2. Tyrosine-protein kinase JAK2

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

Sh2 domain binding

Specific Function

Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptiv...

Gene Name

JAK2

Uniprot ID

O60674

Uniprot Name

Tyrosine-protein kinase JAK2

Molecular Weight

130672.475 Da

References

1. FDA Approved Drug Products: CIBINQO (abrocitinib) tablets, for oral use [Link]

Details3. Tyrosine-protein kinase JAK3

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

Protein tyrosine kinase activity

Specific Function

Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a...

Gene Name

JAK3

Uniprot ID

P52333

Uniprot Name

Tyrosine-protein kinase JAK3

Molecular Weight

125097.565 Da

References

1. FDA Approved Drug Products: CIBINQO (abrocitinib) tablets, for oral use [Link]

Details4. Non-receptor tyrosine-protein kinase TYK2

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

Protein tyrosine kinase activity

Specific Function

Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.

Gene Name

TYK2

Uniprot ID

P29597

Uniprot Name

Non-receptor tyrosine-protein kinase TYK2

Molecular Weight

133648.77 Da

References

1. FDA Approved Drug Products: CIBINQO (abrocitinib) tablets, for oral use [Link]

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Drug created at May 20, 2019 14:38 / Updated at February 16, 2023 16:06