Tìm theo
Tofacitinib
Các tên gọi khác (2) :
  • Tasocitinib
  • Tofacitinibum
Thuốc Gốc
Small Molecule
CAS: 477600-75-2
ATC: L04AA29
Tofacitinib is an inhibitor of Janus kinases, a group of intracellular enzymes involved in signaling pathways that affect hematopoiesis and immune cell function. It is approved by the FDA for treatment of moderate to severe rheumatoid arthritis that responds inadequately to methotrexate or in those who are intolerant to methotrexate. 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. Known adverse effects include nausea and headache as well as more serious immunologic and hematological adverse effects. Tofacitinib is marketed under the brand name Xeljanz.
Nhận Dạng Quốc Tế & Đặc Tính Hóa Học
logP
1.808
Dược Lực Học : Tofacitinib targets inflammation present in rheumatoid arthritis by inhibiting the janus kinases involved in the inflammatory response pathway. In placebo controlled trials of rheumatoid arthritis patients receiving 5mg or 10mg of tofacitinib twice daily, higher ACR20 responses were observed within 2 weeks in some patients (with ACR20 being defined as a minimum 20% reduction in joint pain or tenderness and 20% reduction in arthritis pain, patient disability, inflammatory markers, or global assessments of arthritis by patients or by doctors, according to the American College of Rheumatology (ACR) response criteria list), and improvements in physical functioning greater than placebo were also noted. Common known adverse effects of tofacitinib include headaches, diarrhea, nausea, nasopharyngitis and upper respiratory tract infection. More serious immunologic and hematological adverse effects have also been noted resulting in lymphopenia, neutropenia, anemia, and increased risk of cancer and infection. Before initiations of tofacitinib patients should be tested for latent infections of tuberculosis, and should be closely monitored for signs and symptoms of infection (fungal, viral, bacterial, or mycobacterial) during therapy. Therapy is not to be started in the presence of active infection, systemic or localized, and is to be interrupted if a serious infection occurs. Tofacitinib has been associated with an increased risk of lymphomas, such as Epstein-Barr virus associated lymphomas, and other malignancies (including lung, breast, gastric, and colorectal cancers). It is recommended to monitor lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids. Tofacitinib use is associated with a rapid decrease in C-reactive protein (CRP), dose dependent decreases in natural killer cells, and dose dependent increases in B cells. Depression in C-reactive protein levels continue after 2 weeks of tofacitinib discontinuation and suggest that pharmacodynamic activity last longer than pharmacokinetic half life.
Cơ Chế Tác Dụng : Tofacitinib is an inhibitor of Janus kinases, a group of intracellular enzymes involved in signaling pathways that affect hematopoiesis and immune cell function. It is approved by the FDA for treatment of moderate to severe rheumatoid arthritis that responds inadequately to methotrexate or in those who are intolerant to methotrexate. 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. Known adverse effects include nausea and headache as well as more serious immunologic and hematological adverse effects. Tofacitinib is marketed under the brand name Xeljanz. Rheumatoid arthritis is an autoimmune disease characterized by a dysregulation of pro-inflammatory cytokines including IL7, IL15, IL21, IL6, IFN-alpha, and IFN-beta. (3) Cytokines signalling results in tissue inflammation and joint damage by stimulating the recruitment and activation of immune cells via the janus kinase signalling pathway. Tofacitinib is a partial and reversible janus kinase (JAK) inihibitor that will prevent the body from responding to cytokine signals. By inhibiting JAKs, tofacitinib prevents the phosphorylation and activation of STATs. The JAK-STAT signalling pathway is involved in the transcription of cells involved in hematopoiesis, and immune cell function. Tofacitinib works therapeutically by inhibiting the JAK-STAT pathway to decrease the inflammatory response. However, there is evidence to suggest that it may also achieve efficacy via other pathways as well.
Dược Động Học :
▧ Absorption :
74% oral absorption (absolute bioavailability), with peak plasma concentrations (T max) achieved in 0.5-1 hour. Administration with fatty meals does not alter AUC but reduces Cmax by 32%.
▧ Volume of Distribution :
Vd= 87L after intravenous administration. Distribution is equal between red blood cells and plasma.
▧ Protein binding :
40%, mostly bound to albumin.
▧ Metabolism :
Metabolized in the liver by CYP3A4 and CYP2C19. Metabolites produced are inactive.
▧ Route of Elimination :
70% metabolized in the liver by CYP3A4 (major) and CYP2C19 (minor). Metabolites produced are inactive. 30% renally eliminated as unchanged drug.
▧ Half Life :
~3 hours
Độc Tính : Minimum lethal dose in rat: 500 mg/kg. Maximum asymptomatic dose in non human primate: 40 mg/kg. Lymphatic, immune system, bone marrow and erythroid cell toxicity was seen in animal studies involving rate and monkeys. Doses used in these studies ranged from 1mg/kg/day to 10mg/kg/day, over a duration of 6 weeks to 6 months. Lymphopenia, neutropenia, and anemia is seen in human subjects and may call for an interruption or discontinuation of therapy if severe. Reduced female fertility in rats was seen at exposures 17 times the maximum recommended human dose. Fertility may be impaired in human females and harm may be caused to unborn child. Carcinogenic potential is seen, however evidence for dose dependency is lacking. Because the janus kinase pathway plays a role in stimulating the production of red blood cells and is involved in immune cell function, inhibition of this pathway leads to increased risk of anemia, neutropenia, lymphopenia, cancer and infection. Lymphopenia, neutropenia, and anemia in human subjects may call for an interruption or discontinuation of therapy if severe. Role of JAK inhibition in the development of gastrointestinal perforation is not known.
Chỉ Định : FDA approved for the treatment of moderate to severe rheumatoid arthritis which is resistant or intolerant to methotrexate therapy. It may also be used as an adjunct to methotrexate therapy, or other non-biologic disease-modifying antirheumatic drugs (DMARDS), when methotrexate alone is not sufficient. Tofacitinib has also been investigated as a preventative therapy for kidney transplant rejections, and as a treatment for psoriasis, ulcerative colitis, and ankylosing spondylitis. It is not to be initiated in patients with a history of chronic or recurrent infections, or in the presence of active infection, even if localized, due to reports of serious and sometimes fatal infections (commonly pneumonia, herpes zoster and urinary tract infections). Use of tofacitinib is also discouraged in those who have been, or are likely to be, exposed to TB. An increased likelihood of exposure may be encountered by traveling to certain areas. In addition, tofacitinib is not to be used in patients with severe hepatic impairment, or low hemoglobin (less than 9g/dL). Cautioned is advised when using tofacitinib in patients at risk of gastrointestinal perforation, and in the elderly who are more susceptible to infection.
Tương Tác Thuốc :
  • Abatacept Avoid combination due to the potential increase in tofacitinib related adverse effects.
  • Adalimumab Adalimumab (and other anti-TNF immunosuppressants), when used in combination with tofacitinib, may increase the risk of added immunosuppression. It is recommended to avoid concurrent therapy.
  • ado-trastuzumab emtansine Avoid combination with tofacitinib and other potent immunosuppressants due to the likely enhancement of immunosuppression.
  • Anakinra Avoid combination due to the potential increase in tofacitinib related adverse effects.
  • Antithymocyte globulin Avoid combination due to enhanced immunosuppressive effects.
  • Belatacept Avoid combination due to enhanced immunosuppressive effect of tofacitinib.
  • Belimumab Avoid combination due to enhanced immunosuppressive effect of tofacitinib.
  • Canakinumab Avoid combination with tofacitinib and other potent immunosuppressants due to potential enhancement of immunosuppressant effects.
  • Certolizumab pegol Certolizumab (and other anti-TNF immunosuppressants), when used in combination with tofacitinib, may increase the risk of added immunosuppression. It is recommended to avoid concurrent therapy.
  • Clozapine Avoid combination due to the increased risk of clozapine induced agranulocytosis.
  • Cyclosporine Cyclosporin (and other strong immunosuppressants), when used in combination with tofacitinib, may increase the risk of added immunosuppression and infection. It is recommended to avoid concurrent therapy.
  • Deferasirox Tofacitinib (and other CYP3A4 substrates), when used in combination with deferasirox, may experience a decrease in concentration. It is recommended to monitor therapy.
  • Denosumab Denosumab, when used in combination with tofacitinib, may increase tofaciitinib toxicity and worsen side effects. It may specifically increase the risk of serious infection. It is recommended to monitor therapy.
  • Etanercept Etanercept increases the risk of added immunosuppression. It is recommended to avoid concurrent therapy.
  • Fluconazole Fluconazole (and other strong CYP2C19 inhibitors and moderate CYP3A4 inhibitors), when used in combination with tofacitinib, may increase tofacitinib concentration. It is recommended to modify therapy by reducing the adult dose of tofacitinib from 5mg twice a day to 5mg daily.
  • Gemtuzumab ozogamicin Avoid combination due to enhancement of immunosuppressants.
  • Glatiramer Acetate Avoid combination due to enhanced immunosuppressive effect of tofacitinib.
  • golimumab Golimumab, and other anti-TNF immunosuppressants, when used in combination with tofacitinib, may increase the serum concentration of tofacitinib, and increase tofacitinib associated side effects and immunosuppresion. It is recommended to avoid concurrent therapy.
  • Homoharringtonine Avoid combination with tofacitinib and other potent immunosuppressants as there is potential to increase the immunosuppressant effects. Other less potent immunosuppressants such as methotrexate, at antirheumatic doses, and other non-disease modifying antirheumatic drugs (non-DMARDs) can be combined.
  • Ibritumomab Avoid combination due to enhanced immunosuppressive effect of tofacitinib.
  • Infliximab Avoid combination with infliximab and other anti-TNF drugs due to the potential enhancement of tofacitinib related adverse effects.
  • Ivacaftor Ivacaftor, when used in combination with tofacitinib, may increase tofaciitinib concentrations, It is recommended to monitor therapy for signs of toxicity or worsened side effects.
  • Leflunomide Leflunomide may experience an increase in toxicity and adverse effects (ie. pancytopenia, agranulocytosis, thrombocytopenia). It is recommended to adjust therapy by forgoing a leflunomide loading dose, and to monitor for bone marrow suppression monthly.
  • Mifepristone Mifepristone, when used in combination with tofacitinib, may increase tofacitinib concentrations. It is recommended to adjust therapy by using a minimized dose of tofacitinib, and monitoring for increased tofacitinib concentrations and signs of toxicity, during and 2 weeks after discontinuation of mifepristone therapy.
  • Natalizumab Avoid combination due to the increased risk of infection.
  • Obinutuzumab Avoid combination due to enhanced immunosuppressive effect.
  • Omalizumab Avoid combination due to enhanced immunosuppressive effect of tofacitinib.
  • Pegaspargase Avoid combination due to enhanced immunosuppressive effect of tofacitinib.
  • Phenytoin Avoid combination with phenytoin and other strong CYP3A4 inducers due to the potential decrease in tofacitinib serum levels.
  • Pimecrolimus Avoid combination due to the potential increase in immunosuppressant associated adverse effects.
  • Rifampicin Rifampin (and other potent CYP3A4 inducers), when used in combination with tofacitinib, may decrease tofacitinib toxicity.
  • Rituximab Avoid combination due to the potential increase in tofacitinib related adverse effects.
  • Roflumilast Roflumilast, when used in combination with tofacitinib, may increase the immunosuppressive effect of tofaciitinib and other immunosuppressive agents. It is recommended to modify therapy.
  • Sitaxentan Sitaxentan (moderate CYP3A4 inhibitors, strong CYP2C19 inhbitors), when used in combination with tofacitinib, may increase tofaciitinib serum concentration toxicity and adverse effects. It is recommended to adjust therapy by reducing the adult dose of tofacitinib from 5mg twice a day to 5 mg daily.
  • Tacrolimus Avoid combination due to the potential increase in immunosuppressant associated adverse effects.
  • Tocilizumab Avoid combination due to the potential increase in tofacitinib related adverse effects.
  • Trastuzumab Trastuzumab, when used in combination with tofacitinib, may increase tofacitinib adverse effects, ie. neutropenic effects. It is recommended to monitor therapy.
Liều Lượng & Cách Dùng : Tablet - Oral - 5 mg
Dữ Kiện Thương Mại
Nhà Sản Xuất
  • Công ty : Pfizer
    Sản phẩm biệt dược : Xeljanz
Tài Liệu Tham Khảo Thêm
drugbank
http://www.drugbank.ca/drugs/DB08895
KEGG Drug
http://www.genome.jp/dbget-bin/www_bget?drug:D09970
National Drug Code Directory
http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/63539-012-02
Wikipedia
http://en.wikipedia.org/wiki/Tofacitinib
RxList
http://www.rxlist.com/xeljanz-drug.htm
PDRhealth
http://www.pdrhealth.com/info/v1us/tofacitinib
Drugs.com
http://www.drugs.com/xeljanz.html
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