U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C16H20N6O.C6H8O7
Molecular Weight 504.4931
Optical Activity ( + )
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TOFACITINIB CITRATE

SMILES

OC(=O)CC(O)(CC(O)=O)C(O)=O.C[C@@H]1CCN(C[C@@H]1N(C)C2=NC=NC3=C2C=CN3)C(=O)CC#N

InChI

InChIKey=SYIKUFDOYJFGBQ-YLAFAASESA-N
InChI=1S/C16H20N6O.C6H8O7/c1-11-5-8-22(14(23)3-6-17)9-13(11)21(2)16-12-4-7-18-15(12)19-10-20-16;7-3(8)1-6(13,5(11)12)2-4(9)10/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20);13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)/t11-,13+;/m1./s1

HIDE SMILES / InChI
Molecular Formula C6H8O7
Molecular Weight 192.1235
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE
Molecular Formula C16H20N6O
Molecular Weight 312.3696
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 2 / 2
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment: description was created based on several sources, including https://www.scribd.com/doc/296556203/A-Review-of-Tofacitinib-Drugs-Pros-and-Cons-of-Pharmaceuticals

Tofacitinib is an orally available inhibitor of Janus kinases (JAK), with immunomodulatory and anti-inflammatory activities. Upon administration, tofacitinib binds to JAK and prevents the activation of the JAK-signal transducers and activators of transcription (STAT) signaling pathway. This may decrease the production of pro-inflammatory cytokines, such as interleukin (IL)-6, -7, -15, -21, interferon-alpha and -beta, and may prevent both an inflammatory response and the inflammation-induced damage caused by certain immunological diseases. JAK kinases are intracellular enzymes involved in signaling pathways affecting hematopoiesis, immunity and inflammation. Tofacitinib was discovered and developed by the National Institutes of Health and Pfizer. Besides rheumatoid arthritis, tofacitinib has also been studied in clinical trials for the prevention of organ transplant rejection, and the treatment of psoriasis and ulcerative colitis. Patients treated with tofacitinib (XELJANZ) are at increased risk for developing serious infections that may lead to hospitalization or death and adverse reactions. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

CNS Activity

CNS Penetrant
2554
Curator's Comment: Penetration of blood-brain barrier was observed both in tofacitinib treated mice.

Originator

Pfizer|National Institutes of Health
2
Curator's Comment: Tofacitinib (formerly tasocitinib, CP-690,550 is a medicine of the janus kinase (JAK) inhibitor class, discovered and also created by the National Institutes of Health and wellness and also Pfizer. Marketed as Xeljanz and also Jakvinus. # Pfizer and O'Shea's laboratory at the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health

Approval Year

2012
595
Targets

Targets

Primary TargetPharmacologyConditionPotency
Tyrosine-protein kinase JAK1
38
Target ID: P23458
Gene ID: 3716.0
Gene Symbol: JAK1
Target Organism: Homo sapiens (Human)
Inhibitor
8297
 112.0 nM [IC50]
Tyrosine-protein kinase JAK2
55
Target ID: O60674
Gene ID: 3717.0
Gene Symbol: JAK2
Target Organism: Homo sapiens (Human)
Inhibitor
8297
 20.0 nM [IC50]
Tyrosine-protein kinase JAK3
27
Target ID: P52333
Gene ID: 3718.0
Gene Symbol: JAK3
Target Organism: Homo sapiens (Human)
Inhibitor
8297
 1.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Secondary
Approved
8429
XELJANZ

Approved Use

Is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). XELJANZ should not be used in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine.

Launch Date

2012
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
44.1 ng/mL
EXPERIMENT
https://www.ncbi.nlm.nih.gov/pubmed/26970526
5 mg 2 times / day steady-state, oral
dose: 5 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
TOFACITINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
38.7 ng/mL
EXPERIMENT
https://www.ncbi.nlm.nih.gov/pubmed/26970526
11 mg 1 times / day steady-state, oral
dose: 11 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
TOFACITINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
41.2 ng/mL
EXPERIMENT
https://www.ncbi.nlm.nih.gov/pubmed/26970526
5 mg single, oral
dose: 5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOFACITINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
36.7 ng/mL
EXPERIMENT
https://www.ncbi.nlm.nih.gov/pubmed/26970526
11 mg single, oral
dose: 11 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOFACITINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
346.9 ng/mL
Clinical Trial
https://clinicaltrials.gov/ct2/show/NCT01743677
100 mg single, oral
dose: 100 mg
route of administration: oral
experiment type: single
co-administered:
TOFACITINIB plasma
Homo sapiens
population: healthy
age:
sex:
food status:
565 ng/mL
Clinical Trial
https://clinicaltrials.gov/ct2/show/NCT01743677
100 mg single, oral
dose: 100 mg
route of administration: oral
experiment type: single
co-administered:
TOFACITINIB plasma
Homo sapiens
population: healthy
age:
sex:
food status:
647.4 ng/mL
Clinical Trial
https://clinicaltrials.gov/ct2/show/NCT01743677
100 mg single, oral
dose: 100 mg
route of administration: oral
experiment type: single
co-administered:
TOFACITINIB plasma
Homo sapiens
population: healthy
age:
sex:
food status:
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
266.1 ng × h/mL
EXPERIMENT
https://www.ncbi.nlm.nih.gov/pubmed/26970526
5 mg 2 times / day steady-state, oral
dose: 5 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
TOFACITINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
272.9 ng × h/mL
EXPERIMENT
https://www.ncbi.nlm.nih.gov/pubmed/26970526
11 mg 1 times / day steady-state, oral
dose: 11 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
TOFACITINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
247.9 ng × h/mL
EXPERIMENT
https://www.ncbi.nlm.nih.gov/pubmed/26970526
5 mg single, oral
dose: 5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOFACITINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
259.8 ng × h/mL
EXPERIMENT
https://www.ncbi.nlm.nih.gov/pubmed/26970526
11 mg single, oral
dose: 11 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOFACITINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
1673.1 ng*h/mL
Clinical Trial
https://clinicaltrials.gov/ct2/show/NCT01743677
100 mg single, oral
dose: 100 mg
route of administration: oral
experiment type: single
co-administered:
TOFACITINIB plasma
Homo sapiens
population: healthy
age:
sex:
food status:
2669.7 ng*h/mL
Clinical Trial
https://clinicaltrials.gov/ct2/show/NCT01743677
100 mg single, oral
dose: 100 mg
route of administration: oral
experiment type: single
co-administered:
TOFACITINIB plasma
Homo sapiens
population: healthy
age:
sex:
food status:
2670.2 ng*h/mL
Clinical Trial
https://clinicaltrials.gov/ct2/show/NCT01743677
100 mg single, oral
dose: 100 mg
route of administration: oral
experiment type: single
co-administered:
TOFACITINIB plasma
Homo sapiens
population: healthy
age:
sex:
food status:
3114.3 ng*h/mL
Clinical Trial
https://clinicaltrials.gov/ct2/show/NCT01743677
100 mg single, oral
dose: 100 mg
route of administration: oral
experiment type: single
co-administered:
TOFACITINIB plasma
Homo sapiens
population: healthy
age:
sex:
food status:
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
3.2 h
EXPERIMENT
https://www.ncbi.nlm.nih.gov/pubmed/26970526
5 mg single, oral
dose: 5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOFACITINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
5.9 h
EXPERIMENT
https://www.ncbi.nlm.nih.gov/pubmed/26970526
11 mg single, oral
dose: 11 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOFACITINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
3 h
DRUG LABEL
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203214s000lbl.pdf
5 mg 2 times / day multiple, oral
dose: 5 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TOFACITINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
3.201 h
Clinical Trial
https://clinicaltrials.gov/ct2/show/NCT01743677
100 mg single, oral
dose: 100 mg
route of administration: oral
experiment type: single
co-administered:
TOFACITINIB plasma
Homo sapiens
population: healthy
age:
sex:
food status:
3.284 h
Clinical Trial
https://clinicaltrials.gov/ct2/show/NCT01743677
100 mg single, oral
dose: 100 mg
route of administration: oral
experiment type: single
co-administered:
TOFACITINIB plasma
Homo sapiens
population: healthy
age:
sex:
food status:
3.32 h
Clinical Trial
https://clinicaltrials.gov/ct2/show/NCT01743677
100 mg single, oral
dose: 100 mg
route of administration: oral
experiment type: single
co-administered:
TOFACITINIB plasma
Homo sapiens
population: healthy
age:
sex:
food status:
3.005 h
Clinical Trial
https://clinicaltrials.gov/ct2/show/NCT01743677
100 mg single, oral
dose: 100 mg
route of administration: oral
experiment type: single
co-administered:
TOFACITINIB plasma
Homo sapiens
population: healthy
age:
sex:
food status:
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
61%
OTHER GOV
https://www.ema.europa.eu/en/documents/assessment-report/xeljanz-epar-public-assessment-report_en.pdf
TOFACITINIB plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
100 mg single, oral
Highest studied dose
Dose: 100 mg
Route: oral
Route: single
Dose: 100 mg
Sources:
https://pubmed.ncbi.nlm.nih.gov/27128212
healthy, 18–45 years
n = 8
Health Status: healthy
Age Group: 18–45 years
Sex: M+F
Population Size: 8
Sources:
https://pubmed.ncbi.nlm.nih.gov/27128212
Other AEs: Nausea...
Other AEs:
Nausea (3 patients)
Sources:
https://pubmed.ncbi.nlm.nih.gov/27128212
30 mg 2 times / day steady, oral
Highest studied dose
Dose: 30 mg, 2 times / day
Route: oral
Route: steady
Dose: 30 mg, 2 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/18557720
unhealthy, 54.2 years ( range: 30–71 years)
n = 10
Health Status: unhealthy
Age Group: 54.2 years ( range: 30–71 years)
Sex: M+F
Population Size: 10
Sources:
https://pubmed.ncbi.nlm.nih.gov/18557720
Disc. AE: Herpes simplex skin chronic ulcers...
Other AEs: Viral infection, Dehydration...
AEs leading to
discontinuation/dose reduction:
Herpes simplex skin chronic ulcers (1 patient)
Other AEs:
Viral infection (severe, 1 patient)
Dehydration (severe, 1 patient)
Sources:
https://pubmed.ncbi.nlm.nih.gov/18557720
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203214s000lbl.pdf
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203214s000lbl.pdf
Other AEs: Infection, Lymphoma...
Other AEs:
Infection (serious)
Lymphoma
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203214s000lbl.pdf
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1216
Health Status: unhealthy
Age Group: adult
Population Size: 1216
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Disc. AE: Pneumonia, Herpes zoster...
AEs leading to
discontinuation/dose reduction:
Pneumonia (2.5%)
Herpes zoster (2.5%)
Aspartate aminotransferase increased (1.5%)
ALT increased (1.5%)
Creatinine increased (1.5%)
Gastrointestinal disorders (1%)
Respiratory disorder (0.4%)
Eye disorders (0.1%)
Skin disorder (1%)
Hepatobiliary disorders (0.3%)
Immune system disorders (0.1%)
Psychiatric disorders (0.1%)
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
10 mg 2 times / day steady, oral
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1214
Health Status: unhealthy
Age Group: adult
Population Size: 1214
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Disc. AE: Pneumonia, Herpes zoster...
AEs leading to
discontinuation/dose reduction:
Pneumonia (2.7%)
Herpes zoster (2.7%)
Aspartate aminotransferase increased (2%)
ALT increased (2%)
Creatinine increased (2%)
Gastrointestinal disorders (1.5%)
Respiratory disorder (0.6%)
Eye disorders (0.2%)
Skin disorder (0.3%)
Vascular disorders (0.3%)
Immune system disorders (0.1%)
Reproductive system and breast disorders (0.1%)
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
AEs

AEs

AESignificanceDosePopulation
Nausea 3 patients
100 mg single, oral
Highest studied dose
Dose: 100 mg
Route: oral
Route: single
Dose: 100 mg
Sources:
https://pubmed.ncbi.nlm.nih.gov/27128212
healthy, 18–45 years
n = 8
Health Status: healthy
Age Group: 18–45 years
Sex: M+F
Population Size: 8
Sources:
https://pubmed.ncbi.nlm.nih.gov/27128212
Herpes simplex skin chronic ulcers 1 patient
Disc. AE
30 mg 2 times / day steady, oral
Highest studied dose
Dose: 30 mg, 2 times / day
Route: oral
Route: steady
Dose: 30 mg, 2 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/18557720
unhealthy, 54.2 years ( range: 30–71 years)
n = 10
Health Status: unhealthy
Age Group: 54.2 years ( range: 30–71 years)
Sex: M+F
Population Size: 10
Sources:
https://pubmed.ncbi.nlm.nih.gov/18557720
Dehydration severe, 1 patient
30 mg 2 times / day steady, oral
Highest studied dose
Dose: 30 mg, 2 times / day
Route: oral
Route: steady
Dose: 30 mg, 2 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/18557720
unhealthy, 54.2 years ( range: 30–71 years)
n = 10
Health Status: unhealthy
Age Group: 54.2 years ( range: 30–71 years)
Sex: M+F
Population Size: 10
Sources:
https://pubmed.ncbi.nlm.nih.gov/18557720
Viral infection severe, 1 patient
30 mg 2 times / day steady, oral
Highest studied dose
Dose: 30 mg, 2 times / day
Route: oral
Route: steady
Dose: 30 mg, 2 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/18557720
unhealthy, 54.2 years ( range: 30–71 years)
n = 10
Health Status: unhealthy
Age Group: 54.2 years ( range: 30–71 years)
Sex: M+F
Population Size: 10
Sources:
https://pubmed.ncbi.nlm.nih.gov/18557720
Lymphoma
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203214s000lbl.pdf
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203214s000lbl.pdf
Infection serious
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203214s000lbl.pdf
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203214s000lbl.pdf
Eye disorders 0.1%
Disc. AE
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1216
Health Status: unhealthy
Age Group: adult
Population Size: 1216
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Immune system disorders 0.1%
Disc. AE
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1216
Health Status: unhealthy
Age Group: adult
Population Size: 1216
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Psychiatric disorders 0.1%
Disc. AE
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1216
Health Status: unhealthy
Age Group: adult
Population Size: 1216
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Hepatobiliary disorders 0.3%
Disc. AE
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1216
Health Status: unhealthy
Age Group: adult
Population Size: 1216
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Respiratory disorder 0.4%
Disc. AE
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1216
Health Status: unhealthy
Age Group: adult
Population Size: 1216
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Gastrointestinal disorders 1%
Disc. AE
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1216
Health Status: unhealthy
Age Group: adult
Population Size: 1216
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Skin disorder 1%
Disc. AE
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1216
Health Status: unhealthy
Age Group: adult
Population Size: 1216
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
ALT increased 1.5%
Disc. AE
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1216
Health Status: unhealthy
Age Group: adult
Population Size: 1216
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Aspartate aminotransferase increased 1.5%
Disc. AE
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1216
Health Status: unhealthy
Age Group: adult
Population Size: 1216
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Creatinine increased 1.5%
Disc. AE
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1216
Health Status: unhealthy
Age Group: adult
Population Size: 1216
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Herpes zoster 2.5%
Disc. AE
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1216
Health Status: unhealthy
Age Group: adult
Population Size: 1216
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Pneumonia 2.5%
Disc. AE
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1216
Health Status: unhealthy
Age Group: adult
Population Size: 1216
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Immune system disorders 0.1%
Disc. AE
10 mg 2 times / day steady, oral
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1214
Health Status: unhealthy
Age Group: adult
Population Size: 1214
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Reproductive system and breast disorders 0.1%
Disc. AE
10 mg 2 times / day steady, oral
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1214
Health Status: unhealthy
Age Group: adult
Population Size: 1214
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Eye disorders 0.2%
Disc. AE
10 mg 2 times / day steady, oral
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1214
Health Status: unhealthy
Age Group: adult
Population Size: 1214
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Skin disorder 0.3%
Disc. AE
10 mg 2 times / day steady, oral
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1214
Health Status: unhealthy
Age Group: adult
Population Size: 1214
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Vascular disorders 0.3%
Disc. AE
10 mg 2 times / day steady, oral
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1214
Health Status: unhealthy
Age Group: adult
Population Size: 1214
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Respiratory disorder 0.6%
Disc. AE
10 mg 2 times / day steady, oral
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1214
Health Status: unhealthy
Age Group: adult
Population Size: 1214
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Gastrointestinal disorders 1.5%
Disc. AE
10 mg 2 times / day steady, oral
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1214
Health Status: unhealthy
Age Group: adult
Population Size: 1214
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
ALT increased 2%
Disc. AE
10 mg 2 times / day steady, oral
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1214
Health Status: unhealthy
Age Group: adult
Population Size: 1214
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Aspartate aminotransferase increased 2%
Disc. AE
10 mg 2 times / day steady, oral
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1214
Health Status: unhealthy
Age Group: adult
Population Size: 1214
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Creatinine increased 2%
Disc. AE
10 mg 2 times / day steady, oral
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1214
Health Status: unhealthy
Age Group: adult
Population Size: 1214
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Herpes zoster 2.7%
Disc. AE
10 mg 2 times / day steady, oral
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1214
Health Status: unhealthy
Age Group: adult
Population Size: 1214
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Pneumonia 2.7%
Disc. AE
10 mg 2 times / day steady, oral
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
unhealthy, adult
n = 1214
Health Status: unhealthy
Age Group: adult
Population Size: 1214
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
Page: p. 122
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG
substrate
1737

inhibitor
1587
inducer
389

substrate
1037

inhibitor
1767
substrate
1217

inhibitor
1852

OverviewOther

Other InhibitorOther SubstrateOther Inducer
CYP2C8
911

UGT1A1
204

UGT1A4
77

UGT1A6
108

UGT1A9
116

UGT2B7
146

CYP2C19
1478

P-gp
1461

OCT2
647

OATP1B1
788

OATP1B3
706
P-gp
1537

CYP2C19
991

BCRP
561

CYP2C8
693

CYP2C18
138

CYP2E1
667

CYP3A5
395

CYP1A1
349

CYP1A2
1054

CYP2A6
543

CYP2B6
664
CYP1A2
701

CYP2B6
547

CYP2C8
168
Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
CYP2C19
1553
 no [IC50 >30 uM]
CYP2C8
965
 no [IC50 >30 uM]
CYP2C9
1819
 no [IC50 >30 uM]
CYP2D6
1891
 no [IC50 >30 uM]
CYP3A4
1925
 no [IC50 >30 uM]
no (co-administration study)
Comment: tofacitinib had no substatial effect on the exposure of midazolam
Page: 7, 9, 33
CYP1A2
1692
 no
CYP2B6
1001
 no
CYP2C8
965
 no
CYP2C9
1819
 no
OATP1B3
715
 no
UGT1A1
254
 no
UGT1A4
80
 no
UGT1A6
141
 no
UGT1A9
121
 no
UGT2B7
157
 no
OCT2
648
 weak [IC50 150 uM]
P-gp
1650
 weak [IC50 311 uM]
OATP1B1
803
 weak [IC50 55.3 uM]
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
CYP1A1
349
 minor
CYP1A2
1054
 minor
CYP2A6
543
 minor
CYP2B6
664
 minor
CYP2C18
138
 minor
CYP2C8
693
 minor
CYP2C9
1037
 minor
CYP2D6
1217
 minor
CYP2E1
667
 minor
CYP3A5
395
 minor
BCRP
561
 no
CYP2C19
991
 yes
yes (co-administration study)
Comment: fluconazole increased tofactinib AUC by 79% and Cmax by 27%;
Page: 6, 8, 32, 89
CYP3A4
1737
 yes
yes (co-administration study)
Comment: ketoconazole increased tofacitinib AUC by 103% and Cmax by 16%; fluconazole increased tofactinib AUC by 79% and Cmax by 27%; rifampin decreased tofacitinib AUC by 84% and Cmax by 74%
Page: 6, 8, 32, 89
P-gp
1537
 yes
yes (co-administration study)
Comment: cyclosporine increased tofacitinib AUC by 73% and decreased Cmax by 17%; tofacitinib coadministration with cyclosproine is not recommended
Page: 6, 9, 33
Sourcing

Sourcing

Vendor/AggregatorIDURL
ChEBI
CHEBI:71200
https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:71200
MolPort
MolPort-006-393-346
https://www.molport.com/shop/molecule-link/MolPort-006-393-346
Selleck Chemicals
tofacitinib-cp-690550
http://www.selleckchem.com/products/tofacitinib-cp-690550.html
ZINC
ZINC000003818808
http://zinc15.docking.org/substances/ZINC000003818808
eMolecules
28294753
https://www.emolecules.com/cgi-bin/more?vid=28294753
PubMed

PubMed

TitleDatePubMed
Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.
2003 Oct 31
Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550).
2008 Dec 25
Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains.
2009 Mar 20
Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection.
2010 Dec 23
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
2010 Nov 24
Comprehensive analysis of kinase inhibitor selectivity.
2011 Oct 30
Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity.
2011 Oct 30
A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery.
2013 Apr 15
Clinical utility of the oral JAK inhibitor tofacitinib in the treatment of rheumatoid arthritis.
2013 Nov 15
JAK inhibitors: treatment efficacy and safety profile in patients with psoriasis.
2014
The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis.
2015 Jun
Patents

Patents

06965027
2
07301023
2
07432370
2
07803805
2
08232394
2
08299084
2
08309716
2
08541426
2
20030073719
2

Sample Use Guides

In Vivo Use Guide
Recommended dose of XELJANZ is 5 mg twice daily. Recommended dose of XELJANZ XR is 11 mg once daily. Recommended dose in patients with moderate and severe renal impairment and moderate hepatic impairment is XELJANZ 5 mg once daily. Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended.
Route of Administration: Oral
In Vitro Use Guide
0-4000 nM tofacitinib was used in human T blasts cell to measure IL-2-dependent proliferation. CP-690550 (tofacitinib) was added to freshly plated cells and cultured for 4 days.
Substance Class Chemical
Created
by admin
on Fri Dec 15 18:46:21 GMT 2023
Edited
by admin
on Fri Dec 15 18:46:21 GMT 2023
Record UNII
O1FF4DIV0D
Record Status Validated (UNII)
Record Version
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Name Type Language
TOFACITINIB CITRATE
DASH   ORANGE BOOK   USAN   WHO-DD  
USAN  
Official Name English
TASOCITINIB CITRATE
Common Name English
TOFACITINIB CITRATE [USAN]
Common Name English
XELJANZ XR
Brand Name English
Tofacitinib citrate [WHO-DD]
Common Name English
1-PIPERIDINEPROPANENITRILE, 4-METHYL-3-(METHYL-7H-PYRROLO(2,3-D)PYRIMIDIN-4-YLAMINO)-.BETA.-OXO-, (3R,4R)-, 2-HYDROXY-1,2,3-PROPANETRICARBOXYLATE (1:1)
Systematic Name English
TASOCITINIB MONOCITRATE
Common Name English
TOFACITINIB MONOCITRATE [MI]
Common Name English
CP-690550 CITRATE
Common Name English
TOFACITINIB CITRATE [JAN]
Common Name English
3-((3R,4R)-4-METHYL-3-(METHYL(7H-PYRROLO(2,3-D)PYRIMIDIN-4-YL)AMINO)PIPERIDIN-1-YL)-3-OXO-PROPANENITRILE2-HYDROXYPROPANE-1,2,3-TRICARBOXYLATE (1:1)
Common Name English
XELJANZ
Brand Name English
TOFACITINIB CITRATE [ORANGE BOOK]
Common Name English
CP-690,550-10
Code English
CP-690550-10
Code English
CP-690
Common Name English
Classification Tree Code System Code
EMA ASSESSMENT REPORTS XELJANZ (REFUSED: ARTHRITIS, RHEUMATOID)
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
NCI_THESAURUS C1967
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
Code System Code Type Description
PUBCHEM
10174505
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
PRIMARY
EPA CompTox
DTXSID80202404
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
PRIMARY
NCI_THESAURUS
C95801
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
PRIMARY
JAPANESE REVIEW
XELJANZ
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
PRIMARY APPROVED MARCH 2013
MERCK INDEX
m10931
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
PRIMARY Merck Index
EVMPD
SUB33105
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
PRIMARY
FDA UNII
O1FF4DIV0D
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
PRIMARY
DRUG BANK
DBSALT000180
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
PRIMARY
RXCUI
1358492
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
PRIMARY RxNorm
USAN
WW-12
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
PRIMARY
DAILYMED
O1FF4DIV0D
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
PRIMARY
CHEBI
71197
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
PRIMARY
SMS_ID
100000126136
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
PRIMARY
CAS
540737-29-9
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
PRIMARY
ChEMBL
CHEMBL221959
Created by admin on Fri Dec 15 18:46:21 GMT 2023 , Edited by admin on Fri Dec 15 18:46:21 GMT 2023
PRIMARY
Related Record Type Details
Structure of ANHYDROUS CITRIC ACID
PARENT -> SALT/SOLVATE
Structure of TOFACITINIB
PARENT -> SALT/SOLVATE
Related Record Type Details
Structure of EPITOFACITINIB, (3R,4S)-
IMPURITY -> PARENT
Structure of (3R,4R)-3-[(6-Amino-4-pyrimidinyl)methylamino]-4-methyl-β-oxo-1-piperidinepropanenitrile
IMPURITY -> PARENT
Structure of Tofacitinib N-Oxide
IMPURITY -> PARENT
Structure of N-METHYL-N-((3R,4R)-4-METHYLPIPERIDIN-3-YL)-7H-PYRROLO(2,3-D)PYRIMIDIN-4-AMINE
IMPURITY -> PARENT
Structure of BUTYL 3-((3R,4R)-4-METHYL-3-(METHYL(7H-PYRROLO(2,3-D)PYRIMIDIN-4-YL)AMINO)PIPERIDIN-1-YL)-3-OXOPROPANOATE
IMPURITY -> PARENT
Structure of EPITOFACITINIB, (3S,4R)-
IMPURITY -> PARENT
Structure of N-METHYL-N-((3R,4R)-4-METHYL-1-(7H-PYRROLO(2,3-D)PYRIMIDIN-4-YL)PIPERIDIN-3-YL)-7H-PYRROLO(2,3-D)PYRIMIDIN-4-AMINE
IMPURITY -> PARENT
Structure of 5,6-DIHYDRO TOFACITINIB
IMPURITY -> PARENT
Structure of TOFACITINIB, (3S,4S)-
IMPURITY -> PARENT
Related Record Type Details
Structure of TOFACITINIB
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