Details of the Drug

General Information of Drug (ID: DMBS370)

Drug Name

Tofacitinib

Synonyms

Tasocitinib; 477600-75-2; 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile; CP-690550; CP 690550; racemic-tofacitinib; 1259404-17-5; tofacitinibum; CP-690,550; UNII-87LA6FU830; 3-((3R,4R)-rel-4-Methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile; 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile; Tofacitinib (CP-690550,Tasocitinib); CHEMBL221959; CHEBI:71200; Xeljanz (TN)

Indication

Disease Entry	ICD 11	Status	REF
Rheumatoid arthritis	FA20	Approved	[1], [2], [3]

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

312.37

Topological Polar Surface Area (xlogp)

1.5

Rotatable Bond Count (rotbonds)

Hydrogen Bond Donor Count (hbonddonor)

Hydrogen Bond Acceptor Count (hbondacc)

ADMET Property

Clearance: The drug present in the plasma can be removed from the body at the rate of 5.88 mL/min/kg [4]
Unbound Fraction: The unbound fraction of drug in plasma is 0.6% [4]
Vd: Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma 1.24 L/kg [4]

Chemical Identifiers

Formula: C16H20N6O
IUPAC Name: 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile
Canonical SMILES: C[C@@H]1CCN(C[C@@H]1N(C)C2=NC=NC3=C2C=CN3)C(=O)CC#N
InChI: InChI=1S/C16H20N6O/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/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20)/t11-,13+/m1/s1
InChIKey: UJLAWZDWDVHWOW-YPMHNXCESA-N

Cross-matching ID

PubChem CID: 9926791
ChEBI ID: CHEBI:71200
CAS Number: 477600-75-2
DrugBank ID: DB08895
TTD ID: D0EG1I
INTEDE ID: DR1610
ACDINA ID: D00683

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Janus kinase 3 (JAK-3)	TTT7PJU	JAK3_HUMAN	Modulator	[2]

------------------------------------------------------------------------------------

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[5]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Substrate	[5]

------------------------------------------------------------------------------------

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This Drug

Molecular Expression Atlas of This Drug

The Studied Disease

Rheumatoid arthritis

ICD Disease Classification

FA20

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Janus kinase 3 (JAK-3)	DTT	JAK3	4.94E-03	0.28	1.41
Mephenytoin 4-hydroxylase (CYP2C19)	DME	CYP2C19	3.82E-03	1.37E-01	1.05E+00
Mephenytoin 4-hydroxylase (CYP2C19)	DME	CYP2C19	3.09E-05	-6.05E-01	-3.19E+00
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	2.51E-01	8.39E-02	5.00E-01
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	1.93E-04	-6.16E-01	-2.64E+00

Molecular Expression Atlas (MEA)

MEA Detail

Jump to Detail Molecular Expression Atlas of This Drug

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Tofacitinib (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Ivosidenib	DM8S6T7	Moderate	Increased metabolism of Tofacitinib caused by Ivosidenib mediated induction of CYP450 enzyme.	Acute myeloid leukaemia [2A60]	[31]
Arn-509	DMT81LZ	Major	Increased metabolism of Tofacitinib caused by Arn-509 mediated induction of CYP450 enzyme.	Acute myeloid leukaemia [2A60]	[31]
Troleandomycin	DMUZNIG	Major	Decreased metabolism of Tofacitinib caused by Troleandomycin mediated inhibition of CYP450 enzyme.	Bacterial infection [1A00-1C4Z]	[31]
Pexidartinib	DMS2J0Z	Moderate	Increased metabolism of Tofacitinib caused by Pexidartinib mediated induction of CYP450 enzyme.	Bone/articular cartilage neoplasm [2F7B]	[31]
Tucatinib	DMBESUA	Major	Decreased metabolism of Tofacitinib caused by Tucatinib mediated inhibition of CYP450 enzyme.	Breast cancer [2C60-2C6Y]	[31]
Osilodrostat	DMIJC9X	Moderate	Decreased metabolism of Tofacitinib caused by Osilodrostat mediated inhibition of CYP450 enzyme.	Cushing syndrome [5A70]	[32]
Lumacaftor	DMCLWDJ	Major	Increased metabolism of Tofacitinib caused by Lumacaftor mediated induction of CYP450 enzyme.	Cystic fibrosis [CA25]	[31]
MK-8228	DMOB58Q	Moderate	Decreased metabolism of Tofacitinib caused by MK-8228 mediated inhibition of CYP450 enzyme.	Cytomegaloviral disease [1D82]	[31]
Stiripentol	DMMSDOY	Moderate	Decreased metabolism of Tofacitinib caused by Stiripentol mediated inhibition of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[31]
Cobicistat	DM6L4H2	Major	Decreased metabolism of Tofacitinib caused by Cobicistat mediated inhibition of CYP450 enzyme.	Human immunodeficiency virus disease [1C60-1C62]	[31]
Berotralstat	DMWA2DZ	Moderate	Decreased metabolism of Tofacitinib caused by Berotralstat mediated inhibition of CYP450 enzyme.	Innate/adaptive immunodeficiency [4A00]	[31]
Ceritinib	DMB920Z	Major	Decreased metabolism of Tofacitinib caused by Ceritinib mediated inhibition of CYP450 enzyme.	Lung cancer [2C25]	[31]
Idelalisib	DM602WT	Major	Decreased metabolism of Tofacitinib caused by Idelalisib mediated inhibition of CYP450 enzyme.	Mature B-cell leukaemia [2A82]	[31]
Dabrafenib	DMX6OE3	Moderate	Increased metabolism of Tofacitinib caused by Dabrafenib mediated induction of CYP450 enzyme.	Melanoma [2C30]	[31]
Siponimod	DM2R86O	Major	Additive immunosuppressive effects by the combination of Tofacitinib and Siponimod.	Multiple sclerosis [8A40]	[31]
Ozanimod	DMT6AM2	Major	Additive immunosuppressive effects by the combination of Tofacitinib and Ozanimod.	Multiple sclerosis [8A40]	[33]
Netupitant	DMEKAYI	Moderate	Decreased metabolism of Tofacitinib caused by Netupitant mediated inhibition of CYP450 enzyme.	Nausea/vomiting [MD90]	[31]
Abametapir	DM2RX0I	Moderate	Decreased metabolism of Tofacitinib caused by Abametapir mediated inhibition of CYP450 enzyme.	Pediculosis [1G00]	[34]
Lefamulin	DME6G97	Moderate	Decreased metabolism of Tofacitinib caused by Lefamulin mediated inhibition of CYP450 enzyme.	Pneumonia [CA40]	[35]
Enzalutamide	DMGL19D	Major	Increased metabolism of Tofacitinib caused by Enzalutamide mediated induction of CYP450 enzyme.	Prostate cancer [2C82]	[31]
Anthrax vaccine	DM9GSWY	Moderate	Antagonize the effect of Tofacitinib when combined with Anthrax vaccine.	Sepsis [1G40-1G41]	[36]
Voxelotor	DMCS6M5	Moderate	Decreased metabolism of Tofacitinib caused by Voxelotor mediated inhibition of CYP450 enzyme.	Sickle-cell disorder [3A51]	[31]
Telotristat ethyl	DMDIYFZ	Moderate	Increased metabolism of Tofacitinib caused by Telotristat ethyl mediated induction of CYP450 enzyme.	Small intestine developmental anomaly [DA90]	[33]
Larotrectinib	DM26CQR	Moderate	Decreased metabolism of Tofacitinib caused by Larotrectinib mediated inhibition of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[31]
Fostamatinib	DM6AUHV	Moderate	Decreased metabolism of Tofacitinib caused by Fostamatinib mediated inhibition of CYP450 enzyme.	Thrombocytopenia [3B64]	[37]
Elagolix	DMB2C0E	Moderate	Increased metabolism of Tofacitinib caused by Elagolix mediated induction of CYP450 enzyme.	Uterine fibroid [2E86]	[31]
-----------


⏷ Show the Full List of 26 DDI Information of This Drug

Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
FD&C blue no. 2	E00446	2723854	Colorant
Hydrochloric acid	E00015	313	Acidulant
Lactic acid	E00020	612	Acidulant
Sodium benzoate	E00432	517055	Antimicrobial preservative; lubricant
Sucralose	E00370	71485	Flavoring agent
Food blue 1 aluminum lake	E00512	11979396	Colorant
Ammonia	E00007	222	Alkalizing agent
Carmellose sodium	E00625	Not Available	Disintegrant
Eisenoxyd	E00585	56841934	Colorant
Ferrosoferric oxide	E00231	14789	Colorant
Hexahydric alcohol	E00083	5780	Diluent; Flavoring agent; Humectant; Plasticizing agent
Hydroxypropyl cellulose	E00632	Not Available	Binding agent; Coating agent; Emulsifying agent; Film/Membrane-forming agent; Modified-release agent; Suspending agent; Viscosity-controlling agent
Hypromellose	E00634	Not Available	Coating agent
Lactose monohydrate	E00393	104938	Binding agent; Diluent; Dry powder inhaler carrier; Lyophilization aid
Magnesium stearate	E00208	11177	lubricant
Polyethylene glycol 3350	E00652	Not Available	Coating agent; Diluent; Ointment base; Plasticizing agent; Solvent; Suppository base; lubricant
Propylene glycol	E00040	1030	Antimicrobial preservative; Humectant; Plasticizing agent; Solvent
Titanium dioxide	E00322	26042	Coating agent; Colorant; Opacifying agent
Triacetin	E00080	5541	Humectant; Plasticizing agent; Solvent
Water	E00035	962	Solvent
Xylitol	E00136	6912	Coating agent; Diluent; Emollient; Flavoring agent; Humectant
Colcothar yellow	E00436	518696	Colorant
Haematite red	E00236	14833	Colorant
Sorbitan tristearate	E00516	17800859	Dispersing agent; Emulsifying agent; Solubilizing agent; Surfactant; Suspending agent; Vaccine adjuvant
Cellulose acetate	E00702	Not Available	Coating agent; Modified-release agent; Diluent
Cellulose microcrystalline	E00698	Not Available	Adsorbent; Suspending agent; Diluent
Copovidone	E00693	Not Available	Film/membrane-forming agent; Modified-release agent; Binding agent
Hydroxyethyl cellulose	E00700	Not Available	Coating agent; Suspending agent; Binding agent; Viscosity-controlling agent
Shellac	E00695	Not Available	Coating agent; Film/membrane-forming agent; Microencapsulating agent; Modified-release agent
--------------------


⏷ Show the Full List of 29 Pharmaceutical Excipients of This Drug

Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Tofacitinib Citrate eq 10mg base tablet	eq 10mg base	Tablet	Oral
Tofacitinib Citrate eq 22mg base extended release tablet	eq 22mg base	Extended Release Tablet	Oral
Tofacitinib Citrate eq 11mg base extended release tablet	eq 11mg base	Extended Release Tablet	Oral
Tofacitinib Citrate eq 5mg base tablet	eq 5mg base	Tablet	Oral
Tofacitinib Citrate eq 1mg base/ml solution	eq 1mg base/ml	Solution	Oral
Tofacitinib 5 mg tablet	5 mg	Oral Tablet	Oral
Tofacitinib 11 mg tablet	11 mg	24 HR Extended Release Oral Tablet	Oral

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

1	URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5677).
2	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
3	ClinicalTrials.gov (NCT02157012) Evaluation of the Condition of Rheumatoid Arthritis After Treatment. U.S. National Institutes of Health.
4	Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
5	The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a janus kinase inhibitor, in humans. Drug Metab Dispos. 2014 Apr;42(4):759-73.
6	Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
7	Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
8	Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
9	Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
10	Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
11	Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
12	Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
13	The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
14	Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
15	High-dose rabeprazole/amoxicillin therapy as the second-line regimen after failure to eradicate H. pylori by triple therapy with the usual doses of a proton pump inhibitor, clarithromycin and amoxicillin. Hepatogastroenterology. 2003 Nov-Dec;50(54):2274-8.
16	Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes. Arch Biochem Biophys. 1997 Oct 1;346(1):161-9.
17	Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006 Mar 13;25(11):1679-91.
18	CYP2C19*17 is associated with decreased breast cancer risk. Breast Cancer Res Treat. 2009 May;115(2):391-6.
19	Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
20	Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1995 Dec;353(1):116-21.
21	Diclofenac and its derivatives as tools for studying human cytochromes P450 active sites: particular efficiency and regioselectivity of P450 2Cs. Biochemistry. 1999 Oct 26;38(43):14264-70.
22	A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998 May;32(5):554-63.
23	Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001 Feb;120(2):525-33.
24	Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
25	URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2049).
26	Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
27	Selective JAK inhibitors in development for rheumatoid arthritis. Expert Opin Investig Drugs. 2014 Aug;23(8):1067-77.
28	Clinical pipeline report, company report or official report of Aclaris Therapeutics.
29	ClinicalTrials.gov (NCT03759340) ATI-502 Topical Solution for the Treatment of Alopecia Areata (AA), Alopecia Universalis (AU) and Alopecia Totalis (AT). U.S. National Institutes of Health.
30	Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 1.Expert Opin Ther Pat. 2017 Feb;27(2):127-143.
31	Cerner Multum, Inc. "Australian Product Information.".
32	Product Information. Isturisa (osilodrostat). Recordati Rare Diseases Inc, Lebanon, NJ.
33	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
34	Product Information. Xeglyze (abametapir topical). Dr. Reddy's Laboratories Inc, Upper Saddle River, NJ.
35	Product Information. Xenleta (lefamulin). Nabriva Therapeutics US, Inc., King of Prussia, PA.
36	CDC. Centers for Disease Control and Prevention/ "Recommendations of the advisory committtee on immunization practices (ACIP): use of vaccines and immune globulins in persons with altered immunocompetence." MMWR Morb Mortal Wkly Rep 42(RR-04) (1993): 1-18. [PMID: 20300058]
37	Product Information. Tavalisse (fostamatinib). Rigel Pharmaceuticals, South San Francisco, CA.