tofacitinib

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Ligands
tofacitinib

GtoPdb Ligand ID: 5677

Synonyms: CP-690,550 | CP-690550 | tasocitinib | Xeljanz®

tofacitinib is an approved drug (FDA (2012), EMA (2017))

Compound class: Synthetic organic

Comment: Tofacitinib is an orally active, Type-1 Janus kinase (JAK) inhibitor and it was first approved by the US FDA in 2012. Tofacitinib was originally described as a selective JAK3 inhibitor [2], but subsequent analysis has revealed it to be a pan-JAK inhibitor, with predominant JAK1 inhibition [3,5].

View interactive charts of activity data across species

View more information in the IUPHAR Pharmacology Education Project: tofacitinib

2D Structure

Physico-chemical Properties

Hydrogen bond acceptors	6
Hydrogen bond donors	1
Rotatable bonds	4
Topological polar surface area	88.91
Molecular weight	312.17
XLogP	1.34
No. Lipinski's rules broken	0

SMILES / InChI / InChIKey

Canonical SMILES	N#CCC(=O)N1CCC(C(C1)N(c1ncnc2c1cc[nH]2)C)C
Isomeric SMILES	N#CCC(=O)N1CC[C@H]([C@H](C1)N(c1ncnc2c1cc[nH]2)C)C
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
InChI Key	UJLAWZDWDVHWOW-YPMHNXCESA-N

No information available.

No information available.

Summary of Clinical Use
Tofacitinib was intiailly approved for the treatment of rheumatoid arthritis. Marketed formulations contain tofacitinib citrate (PubChem CID 10174505). In Feb 2016 Xelanj XR® was FDA approved as the first once-daily oral JAK inhibitor for rheumatoid arthritis. In June 2018, FDA approval was expanded to include treatment of patients with moderate to severe ulcerative colitis (UC), subsequent to results from the Phase 3 OCTAVE studies, in which treatment of UC patients with tofacitinib met all primary endpoints and induced significant disase remission [9,12-13]. Xelanj XR® is not approved for UC. A report in JCI Insight in September 2016 suggests that tofacitinib-induced immunosuppression can stimulate significant hair regrowth in patients with the autoimmune condition alopecia areata [8], although more extensive studies would need to be conducted before the drug could be approved for this indication. Click here to link to a list of tofacitinib/alopecia trials registered with ClinicalTrials.gov.

Summary of Clinical Use

Tofacitinib was intiailly approved for the treatment of rheumatoid arthritis. Marketed formulations contain tofacitinib citrate (PubChem CID 10174505).
In Feb 2016 Xelanj XR® was FDA approved as the first once-daily oral JAK inhibitor for rheumatoid arthritis.
In June 2018, FDA approval was expanded to include treatment of patients with moderate to severe ulcerative colitis (UC), subsequent to results from the Phase 3 OCTAVE studies, in which treatment of UC patients with tofacitinib met all primary endpoints and induced significant disase remission [9,12-13]. Xelanj XR® is not approved for UC.

A report in JCI Insight in September 2016 suggests that tofacitinib-induced immunosuppression can stimulate significant hair regrowth in patients with the autoimmune condition alopecia areata [8], although more extensive studies would need to be conducted before the drug could be approved for this indication. Click here to link to a list of tofacitinib/alopecia trials registered with ClinicalTrials.gov.

Mechanism Of Action and Pharmacodynamic Effects
Tofacitinib is a JAK3 inhibitor approved for the treatment of rheumatoid arthritis either on its own or in combination with methotrexate or other nonbiologic disease modifying antirheumatic drugs. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence hematopoiesis and immune cell function, via STATs which modulate gene expression. It is believed that tofacitnib improves disease symptoms by suppressing STAT-1 dependent genes and inhibiting the production of inflammatory mediators in joint tissue. Tofacitinib modulates both innate and adaptive immune responses [7].

Mechanism Of Action and Pharmacodynamic Effects

Tofacitinib is a JAK3 inhibitor approved for the treatment of rheumatoid arthritis either on its own or in combination with methotrexate or other nonbiologic disease modifying antirheumatic drugs. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence hematopoiesis and immune cell function, via STATs which modulate gene expression. It is believed that tofacitnib improves disease symptoms by suppressing STAT-1 dependent genes and inhibiting the production of inflammatory mediators in joint tissue. Tofacitinib modulates both innate and adaptive immune responses [7].

Pharmacokinetics
Absorption/Distribution
Peak plasma concentrations are reached within 0.5-1 hour following oral aministration and patients can be dosed without regard to food. Absolute oral bioavailability of tofacitinib is 74%. Protein binding of tofacitinib is approximately 40%. Binding is predominantly to albumin and not to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma. Tofacitinib exposure is increased when coadministered with potent and moderate inhibitors of cytochrome CYP3A4 (e.g. ketoconazole and fluconazole respectively). Fluconazole is also a potent inhibitor of CYP2C19 and increases tofacitinib exposure. In contrast, tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers such as rifampicin. There is a risk of cumulative immunosuppression when tofacitinib is coadministered with potent immunosuppressive drugs (e.g. azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in rheumatoid arthritis.
Biotransformation/Metabolism
The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19 generating 8 identified metabolites. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to the metabolites, hence the pharmacologic activity of tofacitinib is attributed to the parent molecule.
Elimination
Clearance mechanisms for tofacitinib are approximately 70% via feces and 30% excretion of the parent drug in urine.
Population pharmacokinetics
Population pharmacokinetic analysis in rheumatoid arthritis patients indicates no clinically relevant change in tofacitinib exposure, after accounting for differences in renal function (i.e., creatinine clearance) between patients, based on age, weight, gender and race. The safety and effectiveness of tofacitinib in pediatric patients have not been established. Caution should be used when treating the elderly in relation to risk of infection.
Organ function impairment
No dose adjustment is required in patients with mild hepatic impairment, but the dose should be reduced in patients with moderate hepatic impairment. Data are not available for patients with severe hepatic insufficiency or hepatitis B or C infection. No dose adjustment is required in patients with mild renal impairment but the dose should be reduced in patients with moderate and severe renal impairment.

Pharmacokinetics

Absorption/Distribution

Peak plasma concentrations are reached within 0.5-1 hour following oral aministration and patients can be dosed without regard to food. Absolute oral bioavailability of tofacitinib is 74%. Protein binding of tofacitinib is approximately 40%. Binding is predominantly to albumin and not to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma. Tofacitinib exposure is increased when coadministered with potent and moderate inhibitors of cytochrome CYP3A4 (e.g. ketoconazole and fluconazole respectively). Fluconazole is also a potent inhibitor of CYP2C19 and increases tofacitinib exposure. In contrast, tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers such as rifampicin. There is a risk of cumulative immunosuppression when tofacitinib is coadministered with potent immunosuppressive drugs (e.g. azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in rheumatoid arthritis.

Biotransformation/Metabolism

The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19 generating 8 identified metabolites. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to the metabolites, hence the pharmacologic activity of tofacitinib is attributed to the parent molecule.

Elimination

Clearance mechanisms for tofacitinib are approximately 70% via feces and 30% excretion of the parent drug in urine.

Population pharmacokinetics

Population pharmacokinetic analysis in rheumatoid arthritis patients indicates no clinically relevant change in tofacitinib exposure, after accounting for differences in renal function (i.e., creatinine clearance) between patients, based on age, weight, gender and race. The safety and effectiveness of tofacitinib in pediatric patients have not been established. Caution should be used when treating the elderly in relation to risk of infection.

Organ function impairment

No dose adjustment is required in patients with mild hepatic impairment, but the dose should be reduced in patients with moderate hepatic impairment. Data are not available for patients with severe hepatic insufficiency or hepatitis B or C infection. No dose adjustment is required in patients with mild renal impairment but the dose should be reduced in patients with moderate and severe renal impairment.