摘要 高雄市立鳳山醫院藥劑部藥師陳怡秀 黃肇偉 高雄長庚紀念醫院藥劑部藥師蕭淑珍 嘉義長庚紀念醫院醫師林靖麒 tofacitinib Janus kinase (JAK) inhibitor methotrexate (DMARD) DMARD Janus kinase (JAK) inhibitor tofacitinib 壹 前言 (rheumatoid arthritis) 1 (disease-modifying antirheumatic drugs, DMARD) (anti-tnf-α) (IL-1 IL-6) (T B ) Janus kinase (JAK) tofacitinib 貳 類風濕性關節炎之致病機轉 T B 藥學雜誌 122 27 藥物科學類風濕性關節炎新藥 Tofacitinib
藥Pharmaceutical Sciences 物科學 (cytokines) TNF-α IL-1 IL-6 IL-12 IL-15 IL- 17 IL-18 IL-21 IL-23 γ (macrophagecolony-stimulation factor-1, MCSF-1) KB (receptor activator of nuclear factor kappa-b lignand, RANKL) (osteoclast) 2 JAK/STAT (signaling pathway) JAK Tofacitinib JAK JAK3 IL-2 receptor γ subunit IL-2,4,7,9,15,21 STAT dimer transcription factor ( ) ( ) 參 Tofacitinib 之作用機轉 JAK tyrosine kinase JAK1 JAK2 JAK3 Tyk2 (nonreceptor tyrosine kinases) (intercellular domains) (JAK1/JAK3 JAK1/JAK2 JAK1/ Tyk2 JAK2/JAK2) JAK (polymerization) JAK STATs STATs (dimmer) 3 JAK (subunit) JAK subunit subunit JAK3 IL-2 receptor γ subunit JAK1 IL-2 receptor β subunit 圖一經由不同 JAK 介導的信號路徑 (Signaling Through Different JAK Combinations) 4-6 肆 類風濕性關節炎新藥 Tofacitinib (U.S. FDA) (anti-tnf-α) etanercept adalimumab golimumab IL-6 inhibitor tocilizumab CTLA-4 Ig abatacept B cell rituximab 2012 anti- TNFα (TST, tuberculin skin test) 28 THE JOURNAL OF TAIWAN PHARMACY Vol.31 No.1
(latent tuberculosis infection, LTBI) INH 300 mg rituximab B C B C lamivudine 7 (self-injected infusion) etanercept rituximab (infusion-related reactions, IRRs) diphenhydramine acetaminophen glucocorticoids (tsdmard) JAK-3 tofacitinib 一 臨床療效 Tofacitinib JAK 2013 methotrexate methotrexate 24 8 384 DMARDs (1 mg 3 mg 5 mg 10 mg 15 mg) 藥物科學(interferon-gamma release assays, IGRAs) tofacitinib 40 mg adalimumab 5 mg tofacitinib 12 12 tofacitinib 3 mg 3 mg 5 mg 10 mg 15 mg 39.2% (p = < 0.05) 59.2% (p < 0.0001) 70.5% (p < 0.0001) 71.9% (p < 0.0001) American College of Rheumatology 20% improvement criteria (ACR20) Adalimumab 35.9% (p = 0.105) ACR20 22.0% ACR20 Adalimumab ACR20 12 tofacitinib 9 717 methotrexate 3 6 (5 mg 10 mg) tofacitinib tofacitinib (5 mg 10 mg) tofacitinib adalimumab 40 mg) tofacitinib 5 mg 10 mg ACR20 51.5% 52.6% adalimumab ACR20 47.2% ACR20 28.3% p < 0.001 3 HAQ-DI 6 DAS28-4 (ESR) 2.6 ( tofacitinib 5 mg adalimumab 40 mg p < 0.05 藥學雜誌 122 29
Pharmaceutical Sciences 藥物科學tofacitinib 10 mg [p < 0.001]) methotrexate tofacitinib adalimumab ( ) 10 二 藥物動力學 Tofacitinib (bioavailability) 74% (Tmax) tofacitinib (AUC) tofacitinib Cmax 32% (elimination halflife) 24-48 (steady-state) CYP3A4 CYP2C19 CYP3A4 CYP2C19 ( fluconazole) tofacitinib AUC Cmax tofacitinib 5 mg 70% 30% 三 劑量與使用注意事項 Tofacitinib (Xeljanz) film-coated 5 mg tablets 5 mg 10 mg 5 mg B C 10 (absolute neutrophil count, ANC) < 1000 cells/mm 3 (lymphocyte count) < 500 cells/mm 3 (Hb level) < 9 g/dl ( ) (AST ALT) 3 ( ) 11 (cytopenias) Tofacitinib 103 12 1 8.2.4 ( ) 伍 結語 tofactinib tofacitinib 30 THE JOURNAL OF TAIWAN PHARMACY Vol.31 No.1
藥物科學New Drugs for the Treatment of Rheumatoid Arthritis: Tofacitinib Yi-Shiou Chen 1, Shu-Chen Hsiao 2, Chao-Wei Huang 1, Jing-Chi Lin 3 Department of Pharmacy, Kaohsiung Municipal Feng-Shan Hospital 1 Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital 2 藥學雜誌 122 31 Department of Rheumatology, Allergy, and Immunology, Chiayi Chang Gung Memorial Hospital 3 Abstract Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by cartilage and joints destruction. To treat RA, biological agents (or called biological DMARDs, bdmards) that selectively target either cell-membrane-bound structures or cytokines, are now available. Biological agents are well tolerated but there is higher risk of injectionsite reactions and increased risk of infections, which are major concerns about their longterm treatment. A new small molecule drug has been discovered, tofacitinib, a Janus kinase (JAK) inhibitor. It is designed for the treatment of RA as monotherapy or in combination with methotrexate and/or other non-biological DMARDs. The development is a valuable pharmacological improvement in addition to the current DMARDs and bdmards. 參考資料 : 1. Scott DL, Wolfe F, Huizinga TW: Rheumatoid arthritis. Lancet 2010; 376: 1094-108. 2. 2014; 31(2): 129-136 3. Lundquist LM, Cole SW, Sikes ML: Efficacy and safety of tofacitinib for treatment of rheumatoid arthritis. World J Orthop 2014; 18; 5(4): 504-11. 4. O'Sullivan LA, Liongue C, Lewis RS, et al: Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Mol Immunol 2007; 44(10): 2497-506. 5. Ghoreschi K, Laurence A, O'Shea JJ: Janus kinases in immune cell signaling. Immunol Rev 2009; 228(1): 273-87. 6. Sanjabi S, Zenewicz LA, Kamanaka M, et al: Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL- 10, and IL-22 in immunity and autoimmunity. Curr Opin Pharmacol 2009; 9(4): 447-53. 7. Hamaki T, Kami M, Kusumi E, et al: Prophylaxis of hepatitis B reactivation using lamivudine in a patient receiving rituximab. Am J Hematol 2001; 68: 292-4. 8. Fleischmann R1, Cutolo M, Genovese MC: Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum 2012; 64(3): 617-629. 9. van Vollenhoven RF1, Fleischmann R, Cohen S, et al: ORAL Standard Investigators. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012; 367(6): 508-519. 10. Xeljanz (package insert). New York: Pfizer, 2012. 11. Ni H, Moe S, Myint KT, et al: Oral janus kinase inhibitor for the treatment of rheumatoid arthritis: tofacitinib. ISRN Rheumatol. 2013; 1-9.