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
Weight
Average: 323.42
Monoisotopic: 323.14159611
Chemical Formula
C14H21N5O2S
Synonyms
  • Abrocitinib
  • PF-04965842

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
Contraindications & Blackbox Warnings
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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

TargetActionsOrganism
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 Cmax and AUC of abrocitinib increased dose proportionally up to 200 mg.5

A high-fat meal, high-calorie meal increased AUC by 26% and Cmax by 29%, and prolongs Tmax 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

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.
DrugInteraction
AbataceptThe metabolism of Abrocitinib can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding and thrombocytopenia can be increased when Abciximab is combined with Abrocitinib.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Abrocitinib.
AcenocoumarolThe metabolism of Abrocitinib can be decreased when combined with Acenocoumarol.
AcetohexamideThe metabolism of Abrocitinib can be decreased when combined with Acetohexamide.
Acetyl sulfisoxazoleThe metabolism of Abrocitinib can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acidThe risk or severity of bleeding and thrombocytopenia can be increased when Acetylsalicylic acid is combined with Abrocitinib.
AdalimumabThe metabolism of Abrocitinib can be increased when combined with Adalimumab.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Abrocitinib.
AgomelatineThe metabolism of Abrocitinib can be decreased when combined with Agomelatine.
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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
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CibinqoTablet, film coated200 mg/1OralPfizer Laboratories Div Pfizer Inc2022-02-24Not applicableUS flag
CibinqoTablet, film coated50 mgOralPfizer Europe Ma Eeig2022-01-20Not applicableEU flag
CibinqoTablet, film coated200 mgOralPfizer Europe Ma Eeig2022-01-20Not applicableEU flag
CibinqoTablet, film coated200 mg/1OralU.S. Pharmaceuticals2022-02-24Not applicableUS flag
CibinqoTablet, film coated50 mgOralPfizer Europe Ma Eeig2022-01-20Not applicableEU flag
CibinqoTablet, film coated200 mgOralPfizer Europe Ma Eeig2022-01-20Not applicableEU flag
CibinqoTablet, film coated100 mgOralPfizer Europe Ma Eeig2022-01-20Not applicableEU flag
CibinqoTablet50 mgOralPfizer Canada UlcNot applicableNot applicableCanada flag
CibinqoTablet, film coated100 mgOralPfizer Europe Ma Eeig2022-01-20Not applicableEU flag
CibinqoTablet, film coated50 mgOralPfizer Europe Ma Eeig2022-01-20Not applicableEU flag

Categories

ATC Codes
D11AH08 — Abrocitinib
Drug Categories
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]
ChemSpider
58824300
BindingDB
159748
RxNav
2591476
ChEMBL
CHEMBL3655081
PDBe Ligand
D7D
Wikipedia
Abrocitinib
PDB Entries
6bbu / 6bbv

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentAtopic Dermatitis1
3CompletedTreatmentAllergic Reaction / Atopic Dermatitis / Dermatitis / Genetic Diseases, Inborn / Immune System Diseases / Skin Diseases / Skin Diseases, Eczematous / Skin Diseases, Genetic / Type I Hypersensitivity2
3CompletedTreatmentAtopic Dermatitis4
3RecruitingTreatmentAtopic Dermatitis1
2CompletedTreatmentAtopic Dermatitis2
2CompletedTreatmentChronic Prurigo / Prurigo Nodularis / Pruritus / Pruritus Chronic / Skin Diseases1
2TerminatedTreatmentPsoriasis Vulgaris (Plaque Psoriasis)1
1CompletedBasic ScienceAtopic Dermatitis1
1CompletedBasic ScienceHealthy Subjects (HS)3
1CompletedBasic ScienceHepatic Impairment1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral100 mg
TabletOral200 mg
TabletOral50 mg
Tablet, film coatedOral100 mg
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral200 mg/1
Tablet, film coatedOral200 mg
Tablet, film coatedOral50 mg
Tablet, film coatedOral50 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9549929No2017-01-242034-02-19US flag
US9545405No2017-01-172034-02-19US flag
US9035074No2015-05-192034-02-19US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.42 mg/mLALOGPS
logP0.93ALOGPS
logP0.83ChemAxon
logS-2.9ALOGPS
pKa (Strongest Acidic)11.47ChemAxon
pKa (Strongest Basic)6.45ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area90.98 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity86 m3·mol-1ChemAxon
Polarizability34.18 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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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]
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]
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]
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]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. FDA Approved Drug Products: CIBINQO (abrocitinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. FDA Approved Drug Products: CIBINQO (abrocitinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: CIBINQO (abrocitinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drug Products: CIBINQO (abrocitinib) tablets, for oral use [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. FDA Approved Drug Products: CIBINQO (abrocitinib) tablets, for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: CIBINQO (abrocitinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Secondary active organic cation transmembrane transporter activity
Specific Function
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnico...
Gene Name
SLC22A1
Uniprot ID
O15245
Uniprot Name
Solute carrier family 22 member 1
Molecular Weight
61153.345 Da
References
  1. FDA Approved Drug Products: CIBINQO (abrocitinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
The metabolites of abrocitinib, M1 and M2 are substrates of the OAT3 transporter.
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. FDA Approved Drug Products: CIBINQO (abrocitinib) tablets, for oral use [Link]

Drug created at May 20, 2019 14:38 / Updated at July 08, 2022 22:28