JAK-inhibitors: clinical pharmacology and application perspectives

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

BACKGROUND: For the last decade, physicians and researchers have been actively developing and investigating a novel targeted synthetic disease-modifying antirheumatic drugs. The application of drugs that affect the JAK-STAT pathway and multiple proinflammatory cytokines certainly has great potential for the treatment of different inflammatory diseases. This review provides articles from the past 10 years describing these small-molecule inhibitors: clinical pharmacology, safety, adverse effects and application. There is a growing body of literature that recognises the importance of JAK inhibitors as attractive pharmacological alternative to biologics.

AIM: The article aims to explore clinical pharmacology of JAK inhibitors, safety, drug interactions, comparison with biologic disease-modifying antirheumatic drugs and perspective applications for these drugs.

MATERIALS AND METHODS: The research data in this review is drawn from five main sources: PubMed, Scopus, Medline, GoogleScholar, eLibrary. A search was conducted for the period from 2012 to 2022 in Russian and English, by combinations of words: janus kinase inhibitors, disease-modifying antirheumatic drugs, safety, adverse effects, autoimmune diseases, pharmacokinetics, pharmacodynamics.

RESULTS: The most important clinically relevant findings were that these small-molecule inhibitors have a main advantages like oral administration, rapid therapeutics effect and less of patients-non-responders to therapy. On the other hand, JAK inhibitors have a classic pharmacokinetics and pharmacodynamics, this allows to study such parameters using standard methods.

CONCLUSIONS: In this review, the aim was to assess clinical pharmacology of JAK inhibitors, safety, comparison withbiologic disease-modifying antirheumatic drugs and perspective applications for these drugs. In general, it seems that the safety issues of JAK inhibitors unresolved, in particular the development of thromboembolic complications, infectiousdiseases, and malignancies. This is an important issue for future research.

About the authors

Svetlana A. Doktorova

Immanuel Kant Baltic Federal University

Author for correspondence.
Email: svdoktorova96@gmail.com
ORCID iD: 0000-0001-5858-7877

Clinical Pharmacologist, Postgraduate Student

Russian Federation, Kaliningrad

Vladimir V. Rafalskiy

Immanuel Kant Baltic Federal University

Email: v.rafalskiy@mail.ru
ORCID iD: 0000-0002-2503-9580
SPIN-code: 9424-2840
Scopus Author ID: 15023010400
ResearcherId: G-3172-2013

MD, Dr. Sci. (Med.), Professor, Department of Therapy Medical institute, Director Clinical Trials Center

Russian Federation, Kaliningrad

Yuliya Yu. Grabovetskaya

Immanuel Kant Baltic Federal University

Email: dr.grabovetskaya@mail.ru
ORCID iD: 0000-0003-1758-3065

Chief Rheumatologistof the Kaliningrad Region, Head of the Anticytokine Center of the Regional Clinical Hospital of the Kaliningrad Region, Assistant of the Department of Hospital Therapy

Russian Federation, Kaliningrad

Sergey V. Korenev

Immanuel Kant Baltic Federal University

Email: skorenev@kantiana.ru
ORCID iD: 0000-0003-2310-0576

MD, Dr. Sci. (Med.), Professor, Director of the Medical Institute

Russian Federation, Kaliningrad

References

  1. Gusev NB. Protein kinases: structure, classification, properties and biological role. Soros Educational Journal. 2000;6(12):4–12. (In Russ.)
  2. 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
  3. 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
  4. 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
  5. Ivashkiv LB. Jak-STAT signaling pathways in cells of the immune system. Rev Immunogenet. 2000;2(2):220–230.
  6. 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
  7. 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.
  8. 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
  9. 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
  10. 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
  11. Choy EH. Clinical significance of Janus Kinase inhibitor selectivity. Rheumatology (Oxford). 2019;58(6):953–962.doi: 10.1093/rheumatology/key339
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. 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
  25. 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.
  26. 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.
  27. 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
  28. 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
  29. 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
  30. 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
  31. 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
  32. 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
  33. 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
  34. 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
  35. 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
  36. 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
  37. 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
  38. 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
  39. 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
  40. 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
  41. 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
  42. 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
  43. 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
  44. 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
  45. 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
  46. 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
  47. 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
  48. 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
  49. 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
  50. 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
  51. 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.
  52. 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.
  53. 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
  54. 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
  55. 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
  56. 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
  57. 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
  58. 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
  59. 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

Copyright (c) 2023 Doktorova S.A., Rafalskiy V.V., Grabovetskaya Y.Y., Korenev S.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
 


Согласие на обработку персональных данных с помощью сервиса «Яндекс.Метрика»

1. Я (далее – «Пользователь» или «Субъект персональных данных»), осуществляя использование сайта https://journals.rcsi.science/ (далее – «Сайт»), подтверждая свою полную дееспособность даю согласие на обработку персональных данных с использованием средств автоматизации Оператору - федеральному государственному бюджетному учреждению «Российский центр научной информации» (РЦНИ), далее – «Оператор», расположенному по адресу: 119991, г. Москва, Ленинский просп., д.32А, со следующими условиями.

2. Категории обрабатываемых данных: файлы «cookies» (куки-файлы). Файлы «cookie» – это небольшой текстовый файл, который веб-сервер может хранить в браузере Пользователя. Данные файлы веб-сервер загружает на устройство Пользователя при посещении им Сайта. При каждом следующем посещении Пользователем Сайта «cookie» файлы отправляются на Сайт Оператора. Данные файлы позволяют Сайту распознавать устройство Пользователя. Содержимое такого файла может как относиться, так и не относиться к персональным данным, в зависимости от того, содержит ли такой файл персональные данные или содержит обезличенные технические данные.

3. Цель обработки персональных данных: анализ пользовательской активности с помощью сервиса «Яндекс.Метрика».

4. Категории субъектов персональных данных: все Пользователи Сайта, которые дали согласие на обработку файлов «cookie».

5. Способы обработки: сбор, запись, систематизация, накопление, хранение, уточнение (обновление, изменение), извлечение, использование, передача (доступ, предоставление), блокирование, удаление, уничтожение персональных данных.

6. Срок обработки и хранения: до получения от Субъекта персональных данных требования о прекращении обработки/отзыва согласия.

7. Способ отзыва: заявление об отзыве в письменном виде путём его направления на адрес электронной почты Оператора: info@rcsi.science или путем письменного обращения по юридическому адресу: 119991, г. Москва, Ленинский просп., д.32А

8. Субъект персональных данных вправе запретить своему оборудованию прием этих данных или ограничить прием этих данных. При отказе от получения таких данных или при ограничении приема данных некоторые функции Сайта могут работать некорректно. Субъект персональных данных обязуется сам настроить свое оборудование таким способом, чтобы оно обеспечивало адекватный его желаниям режим работы и уровень защиты данных файлов «cookie», Оператор не предоставляет технологических и правовых консультаций на темы подобного характера.

9. Порядок уничтожения персональных данных при достижении цели их обработки или при наступлении иных законных оснований определяется Оператором в соответствии с законодательством Российской Федерации.

10. Я согласен/согласна квалифицировать в качестве своей простой электронной подписи под настоящим Согласием и под Политикой обработки персональных данных выполнение мною следующего действия на сайте: https://journals.rcsi.science/ нажатие мною на интерфейсе с текстом: «Сайт использует сервис «Яндекс.Метрика» (который использует файлы «cookie») на элемент с текстом «Принять и продолжить».