Ингибиторы JAK: клиническая фармакология и перспективы применения
- Авторы: Докторова С.А.1, Рафальский В.В.1, Грабовецкая Ю.Ю.1, Коренев С.В.1
-
Учреждения:
- Балтийский федеральный университет им. Иммануила Канта
- Выпуск: Том 20, № 4 (2022)
- Страницы: 421-434
- Раздел: Клиническая фармакология
- URL: https://journal-vniispk.ru/RCF/article/view/131536
- DOI: https://doi.org/10.17816/RCF204421-434
- ID: 131536
Цитировать
Аннотация
Актуальность. В последнее десятилетие врачи и исследователи активно разрабатывают и изучают новые таргетные синтетические болезнь-модифицирующие антиревматические препараты. Применение лекарственных средств, влияющих на путь JAK-STAT и множественные провоспалительные цитокины, безусловно, имеет большой потенциал для лечения пациентов с различными аутоиммунными заболеваниями. С каждым годом растет объем литературы, в которой признается важность ингибиторов JAK как фармакологической альтернативы биологическим препаратам.
Цель — описание клинической фармакологии ингибиторов JAK, безопасности, лекарственных взаимодействий, а также сравнения с биологическими болезнь-модифицирующими антиревматическими препаратами и перспектив их применения.
Материалы и методы. Данные исследований в обзоре взяты из пяти основных источников: PubMed, Scopus, Medline, GoogleScholar, eLibrary. Поиск проводился за период с 2012 по 2022 г. на русском и английском языках по сочетаниям слов: ингибиторы янус-киназ, болезнь-модифицирующие антиревматические препараты, безопасность, побочные эффекты, аутоиммунные заболевания, фармакокинетика, фармакодинамика.
Результаты. Наиболее значимым выводом является то, что данные низкомолекулярные ингибиторы имеют преимущества: пероральный прием, быстрое развитие терапевтического эффекта и меньшее количество пациентов, не отвечающих на терапию. С другой стороны, ингибиторы JAK имеют классическую фармакокинетику и фармакодинамику, что позволяет изучать такие параметры стандартными методами.
Заключение. Проведена оценка клинической фармакологии ингибиторов JAK, безопасности, сравнение с биологическими болезнь-модифицирующими антиревматическими препаратами и перспективы применения этих препаратов. В целом, остается нерешенным вопрос безопасности ингибиторов JAK, в частности, развития тромбоэмболических осложнений, инфекционных заболеваний и злокачественных новообразований. Это является важным вопросом для будущих исследований.
Полный текст
Открыть статью на сайте журналаОб авторах
Светлана Алексеевна Докторова
Балтийский федеральный университет им. Иммануила Канта
Автор, ответственный за переписку.
Email: svdoktorova96@gmail.com
ORCID iD: 0000-0001-5858-7877
врач-клинический фармаколог, аспирант
Россия, КалининградВладимир Витальевич Рафальский
Балтийский федеральный университет им. Иммануила Канта
Email: v.rafalskiy@mail.ru
ORCID iD: 0000-0002-2503-9580
SPIN-код: 9424-2840
Scopus Author ID: 15023010400
ResearcherId: G-3172-2013
д-р мед. наук, профессор кафедры терапии Медицинского института, директор Центра клинических исследований
Россия, КалининградЮлия Юрьевна Грабовецкая
Балтийский федеральный университет им. Иммануила Канта
Email: dr.grabovetskaya@mail.ru
ORCID iD: 0000-0003-1758-3065
главный внештатный ревматолог Калининградской области; заведующая Центром антицитокиновой терапии, ассистент кафедры госпитальной терапии Медицинского института
Россия, КалининградСергей Владимирович Коренев
Балтийский федеральный университет им. Иммануила Канта
Email: skorenev@kantiana.ru
ORCID iD: 0000-0003-2310-0576
д-р мед. наук, профессор, директор медицинского института
Россия, КалининградСписок литературы
- Gusev NB. Protein kinases: structure, classification, properties and biological role. Soros Educational Journal. 2000;6(12):4–12. (In Russ.)
- Stark GR, Darnell Jr JE. The JAK-STAT pathway at twenty. Immunity. 2012;36(4):503–514. doi: 10.1016/j.immuni.2012.03.013
- El Jammal T, Sève P, Gerfaud-Valentin M, et al. State of the art: approved and emerging JAK inhibitors for rheumatoid arthritis. Expert Opin Pharmacother. 2021. Vol. 22, No. 2. P. 205–218.doi: 10.1080/14656566.2020.1822325
- López-Sanromán A, Esplugues JV, Domènech E. Pharmacology and safety of tofacitinib in ulcerative colitis. Gastroenterología y Hepatología (English Edition). 2021;44(1):39–48.doi: 10.1016/j.gastrohep.2020.04.012
- Ivashkiv LB. Jak-STAT signaling pathways in cells of the immune system. Rev Immunogenet. 2000;2(2):220–230.
- Nasonov EL, Lila AM. Janus kinase inhibitors in andom-inflammatory rheumatic diseases: new opportunities and prospects. Rheumatology Science and Practice. 2019;57(1):8–16. (In Russ.) doi: 10.14412/1995-4484-2019-8-16
- Hodge JA, Kawabata TT, Krishnaswami S, et al. The mechanism of action of tofacitinib — an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clin Exp Rheumatol. 2016;34(2):318–328.
- Dowty ME, Lin TH, Jesson MI, et al. Janus kinase inhibitors for the treatment of rheumatoid arthritis demonstrate similar profiles of in vitro cytokine receptor inhibition. Pharmacol Res Perspect. 2019;7(6): e00537. doi: 10.1002/prp2.537
- Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: what can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis? Ann Rheum Dis. 2018;77(2):175–187. doi: 10.1136/annrheumdis-2017-211555
- Schwartz DM, Kanno Y, Villarino A, et al. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 2017;16(12):843–862. doi: 10.1038/nrd.2017.201
- Choy EH. Clinical significance of Janus Kinase inhibitor selectivity. Rheumatology (Oxford). 2019;58(6):953–962.doi: 10.1093/rheumatology/key339
- Hutmacher MM, Papp K, Krishnaswami S, et al. Evaluating dosage optimality for tofacitinib, an oral Janus kinase inhibitor, in plaque psoriasis, and the influence of body weight. CPT Pharmacometrics Syst Pharmacol. 2017;6(5):322–330. doi: 10.1002/psp4.12182
- Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723–1736. doi: 10.1056/NEJMoa1606910
- Colombel JF, Osterman MT, Thorpe AJ, et al. Maintenance of remission with tofacitinib therapy in patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2022;20(1):116–125.e5.doi: 10.1016/j.cgh.2020.10.004
- Gilardi D, Gabbiadini R, Allocca M, et al. PK, PD, and interactions: the new scenario with JAK inhibitors and S1P receptor modulators, two classes of small molecule drugs, in IBD. Exp Rev Gastroenterol Hepatol. 2020;14(9):797–806. doi: 10.1080/17474124.2020.1785868
- Mukherjee A, Hazra A, Smith MK, et al. Exposure-response characterization of tofacitinib efficacy in moderate to severe ulcerative colitis: Results from a dose-ranging phase 2 trial. Br J Clin Pharmacol. 2018;84(6):1136–1145. doi: 10.1111/bcp.13523
- Namour F, Fagard L, Van der Aa A, et al. Influence of age and renal impairment on the steady state pharmacokinetics of filgotinib, a selective JAK1 inhibitor. Br J Clin Pharmacol. 2018;84(12):2779–2789. doi: 10.1111/bcp.13726
- Veeravalli V, Dash RP, Thomas JA, et al. Critical assessment of pharmacokinetic drug-drug interaction potential of tofacitinib, baricitinib and upadacitinib, the three approved Janus kinase inhibitors for rheumatoid arthritis treatment. Drug Safety. 2020; 43(8):711–725. doi: 10.1007/s40264-020-00938-z
- Lamba M, Wang R, Fletcher T, et al. Extended-release once-daily formulation of tofacitinib: evaluation of pharmacokinetics compared with immediate-release tofacitinib and impact of food. J Clin Pharmacol. 2016;56(11):1362–1371. doi: 10.1002/jcph.734
- Xu Z, Wang Y, Liu Z, et al. A randomized, crossover, phase I clinical study to evaluate bioequivalence and safety of tofacitinib and Xeljanz® in Chinese healthy subjects. Int Immunopharmacol. 2022;109:108780. doi: 10.1016/j.intimp.2022.108780
- Krishnaswami S, Wang T, Yuan Y, et al. Single- and multiple-dose pharmacokinetics of tofacitinib in healthy Chinese volunteers. Clin Pharmacol Drug Dev. 2015;4(5):395–399. doi: 10.1002/cpdd.202
- Zhao X, Sheng XY, Payne CD, et al. Pharmacokinetics, safety, and tolerability of single- and multiple-dose once-daily baricitinib in healthy Chinese subjects: a randomized placebo controlled study. Clin Pharmacol Drug Dev. 2020;9(8):952–960. doi: 10.1002/cpdd.868
- Bissonnette R, Papp KA, Poulin Y, et al. Topical tofacitinib for atopic dermatitis: a phase II a randomized trial. Br J Dermatol. 2016;175(5):902–911. doi: 10.1111/bjd.14871
- Purohit VS, Ports WC, Wang C, et al. Systemic tofacitinib concentrations in adult patients with atopic dermatitis treated with 2% tofacitinib ointment and application to pediatric study planning. J Clin Pharmacol. 2019;59(6):811–820. doi: 10.1002/jcph.1360
- Nakagawa H, Nemoto O, Igarashi A, et al. Long-term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis. J Dermatol. 2020;47(2):114–120.
- Lindenmann J, Burke DC, Isaacs A. Studies on the production, mode of action and properties of interferon. Br J Exp Pathol. 1957;38(5):551.
- Waterman KC, MacDonald BC, Roy MC. Extrudable core system: development of a single-layer osmotic controlled-release tablet. J Control Release. 2009;134(3):201–206.doi: 10.1016/j.jconrel.2008.11.017
- Ma C, Jairath V, Casteele NV. Pharmacology, efficacy and safety of JAK inhibitors in Crohn’s disease. Best Pract Res Clin Gastroenterol. 2019;38:101606. doi: 10.1016/j.bpg.2019.03.002
- Harigai M, Honda S. Selectivity of Janus kinase inhibitors in rheumatoid arthritis and other immune-mediated inflammatory diseases: is expectation the root of all headache? Drugs. 2020;80(12):1183–1201. doi: 10.1007/s40265-020-01349-1
- Amrhein J, Drynda S, Schlatt L, et al. Tofacitinib and baricitinib are taken up by different uptake mechanisms determining the efficacy of both drugs in RA. Int J Mol Sci. 2020;21(18):6632. doi: 10.3390/ijms21186632
- Dowty ME, Lin J, Ryder TF, et al. The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a Janus kinase inhibitor, in humans. Drug Metab Dispos. 2014;42(4):759–773. doi: 10.1124/dmd.113.054940
- Lawendy N, Lamba M, Chan G, et al. The effect of mild and moderate hepatic impairment on the pharmacokinetics of tofacitinib, an orally active Janus kinase inhibitor. Clin Pharmacol Drug Dev. 2014;3(6):421–427. doi: 10.1002/cpdd.143
- Anderson K, Zheng H, Medzihradsky O, et al. THU0117 Pharmacokinetics and short-term safety of filgotinib, a selective Janus kinase 1 inhibitor, in subjects with moderate hepatic impairment. Ann Rheum Dis. 2019;78(2):331. doi: 10.1136/annrheumdis-2019-eular.2325
- Trueman S, Mohamed MF, Feng T, et al. Characterization of the effect of hepatic impairment on upadacitinib pharmacokinetics. J Clin Pharmacol. 2019;59(9):1188–1194. doi: 10.1002/jcph.1414
- Krishnaswami S, Chow V, Boy M, et al. Pharmacokinetics of tofacitinib, a Janus kinase inhibitor, in patients with impaired renal function and end stage renal disease. J Clin Pharmacol. 2014;54(1):46–52. doi: 10.1002/jcph.178
- Mohamed MF, Trueman S, Feng T, et al. Characterization of the effect of renal impairment on upadacitinib pharmacokinetics. J Clin Pharmacol. 2019;59(6):856–862. doi: 10.1002/jcph.1375
- Menon S, Riese R, Wang R, et al. Evaluation of the effect of tofacitinib on the pharmacokinetics of oral contraceptive steroids in healthy female volunteers. Clin Pharmacol Drug Dev. 2016;5(5):336–342. doi: 10.1002/cpdd.270
- Mohamed MF, Jungerwirth S, Asatryan A, et al. Assessment of effect of CYP3A inhibition, CYP induction, OATP1B inhibition, and high fat meal on pharmacokinetics of the JAK1 inhibitor upadacitinib. Br J Clin Pharmacol. 2017;83(10):2242–2248. doi: 10.1111/bcp.13329
- Posada MM, Cannady EA, Payne CD, et al. Prediction of transporter-mediated drug-drug interactions for baricitinib. Clin Transl Sci. 2017;10(6):509–519. doi: 10.1111/cts.12486
- Begley R, Anderson K, Watkins TR, et al. Lack of drug-drug interaction between filgotinib, a selective jak1 inhibitor, and oral hormonal contraceptives levonorgestrel/ethinyl estradiol in healthy volunteers. Clin Pharmacol Drug Dev. 2021;10(4):376–383. doi: 10.1002/cpdd.870
- Mohamed MF, Coppola S, Feng T, et al. Effect of upadacitinib on the pharmacokinetics of rosuvastatin or atorvastatin in healthy subjects. Clin Pharmacol Drug Dev. 2021;10(11):1335–1344. doi: 10.1002/cpdd.957
- Anderson K, Nelson CH, Gong Q, et al. Assessment of the effect of filgotinib on the pharmacokinetics of atorvastatin, pravastatin, and rosuvastatin in healthy adult participants. Clin Pharmacol Drug Dev. 2022;11(2):235–245. doi: 10.1002/cpdd.1015
- Hsueh CH, Anderson K, Shen G, et al. Evaluation of the potential drug interactions mediated through P-gp, OCT2, and MATE1/2K with filgotinib in healthy subjects. Clin Transl Sci. 2022;15(2):361–370. doi: 10.1111/cts.13152
- Walton A, Paik J, Quebe A, et al. Frequency of prescription claims for drugs that may interact with Janus kinase inhibitors among patients with rheumatoid arthritis in the US. Rheumatol Ther. 2021;8(1):599–607. doi: 10.1007/s40744-020-00275-8
- Dudek P, Fabisiak A, Zatorski H, et al. Efficacy, safety and future perspectives of JAK inhibitors in the IBD treatment. J Clin Med. 2021;10(23):5660. doi: 10.3390/jcm10235660
- Weng C, Xue L, Wang Q, et al. Comparative efficacy and safety of Janus kinase inhibitors and biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and network meta-analysis. Ther Adv Musculoskelet Dis. 2021;13:1759720X21999564. doi: 10.1177/1759720X21999564
- Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386(4):316–326. doi: 10.1056/NEJMoa2109927
- Wang K, Li B, Xie Y, et al. Statin rosuvastatin inhibits apoptosis of human coronary artery endothelial cells through upregulation of the JAK2/STAT3 signaling pathway. Mol Med Rep. 2020;22(3):2052–2062. doi: 10.3892/mmr.2020.11266
- Liao Y, Hu X, Guo X, et al. Promoting effects of IL23 on myocardial ischemia and reperfusion are associated with increased expression of IL17A and upregulation of the JAK2-STAT3signaling pathway. Mol Med Rep. 2017;16(6):9309–9316.doi: 10.3892/mmr.2017.7771
- Nurmohamed M, Choy E, Lula S, et al. The impact of biologics and tofacitinib on cardiovascular risk factors and outcomes in patients with rheumatic disease: a systematic literature review. Drug Saf. 2018;41(5):473–488. doi: 10.1007/s40264-017-0628-9
- FDA [Internet]. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. 2021. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death.
- ema.europa.eu/en [Internet]. EMA starts safety review of Janus kinase inhibitors for inflammatory disorders 11 Feb 2022. Available from: https://www.ema.europa.eu/en/news/ema-starts-safety-review-janus-kinase-inhibitors-inflammatory-disorders.
- Strand V, Ahadieh S, French J, et al. Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials. Arthritis Res Ther. 2015;17:362. doi: 10.1186/s13075-015-0880-2
- Clarke B, Yates M, Adas M, et al. The safety of JAK-1 inhibitors. Rheumatology (Oxford). 2021;60 (Supple 2): ii24–ii30.doi: 10.1093/rheumatology/keaa895
- Kremer JM, Bingham CO 3rd, Cappelli LC, et al. Postapproval comparative safety study of tofacitinib and biological disease-modifying antirheumatic drugs: 5-Year Results from a United States — Based Rheumatoid Arthritis Registry. ACR Open Rheumatol. 2021;3(3):173–184. doi: 10.1002/acr2.11232
- Kavanaugh A, Kremer J, Ponce L, et al. Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a andomized, dose-finding study (DARWIN2). Ann Rheum Dis. 2017;76(6):1009–1019. doi: 10.1136/annrheumdis-2016-210105
- van Vollenhoven R, Takeuchi T, Pangan AL, et al. Efficacy and Safety of Upadacitinib Monotherapy in Methotrexate-naïve patients with Moderately-to-Severely Active Rheumatoid Arthritis (SELECT-EARLY): a multicenter, multi-country, randomized, double-blind, active comparator–controlled trial. Arthritis Rheumatol. 2020;72(10):1607–1620. doi: 10.1002/art.41384
- T Virtanen A, Haikarainen T, Raivola J, et al. Selective JAKinibs: prospects in inflammatory and autoimmune diseases. BioDrugs. 2019;33(1):15–32. doi: 10.1007/s40259-019-00333-w
- Jamilloux Y, El Jammal T, Vuitton L, et al. JAK inhibitors for the treatment of autoimmune and inflammatory diseases. Autoimmun Rev. 2019;18(11):102390. doi: 10.1016/j.autrev.2019.102390
