Top

Published in:

Open Access 01-05-2020 | Pharmacokinetics | Review Article

Clinical Pharmacokinetics of Upadacitinib: Review of Data Relevant to the Rheumatoid Arthritis Indication

Authors: Mohamed-Eslam F. Mohamed, Ben Klünder, Ahmed A. Othman

Published in: Clinical Pharmacokinetics | Issue 5/2020

Abstract

Upadacitinib is a Janus kinase 1 inhibitor developed for treatment of moderate to severe rheumatoid arthritis (RA) and was recently approved by the US Food and Drug Administration for this indication in adults who have had an inadequate response or intolerance to methotrexate. Upadacitinib is currently under regulatory review by other agencies around the world. Ongoing trials are investigating the use of upadacitinib in other inflammatory autoimmune diseases. In this article, we review the clinical pharmacokinetic data available to date for upadacitinib that supported the clinical development program in RA and ultimately regulatory applications for upadacitinib in treatment of patients with moderate to severe RA.

Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci. 2004;117(Pt 8):1281–3. https://doi.org/10.1242/jcs.00963.CrossRefPubMed

O’Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity. 2012;36(4):542–50. https://doi.org/10.1016/j.immuni.2012.03.014.CrossRefPubMedPubMedCentral

Fragoulis GE, McInnes IB, Siebert S. JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis. Rheumatology (Oxford). 2019;58(Suppl_1):i43–54.CrossRef

Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023–38. https://doi.org/10.1016/S0140-6736(16)30173-8.CrossRefPubMed

Burmester GR, Pope JE. Novel treatment strategies in rheumatoid arthritis. Lancet. 2017;389(10086):2338–48. https://doi.org/10.1016/S0140-6736(17)31491-5.CrossRefPubMed

AbbVie. AbbVie receives FDA approval of RINVOQ™ (upadacitinib), an oral JAK inhibitor for the treatment of moderate to severe rheumatoid arthritis. 2019. https://news.abbvie.com/news/press-releases/abbvie-receives-fda-approval-rinvoq-upadacitinib-an-oral-jak-inhibitor-for-treatment-moderate-to-severe-rheumatoid-arthritis.htm. Accessed 28 Nov 2019.

Guttman-Yassky E, Silverberg JI, Thaci D, Hong C-H, Mohamed M-EF, Othman AA, et al. Primary results from a phase 2b, randomized, placebo-controlled trial of upadacitinib for patients with atopic dermatitis [abstract no. #6533]. In: American Academy of Dermatology Annual Meeting; 16–20 Feb 2018; San Diego.

Mohamed MF, Klunder B, Lacerda AP, Othman AA. Exposure-response analyses for upadacitinib efficacy and safety in the Crohn’s disease CELEST study and bridging to the extended-release formulation. Clin Pharmacol Ther. 2019. https://doi.org/10.1002/cpt.1668(epub 2019 Oct 8).CrossRefPubMedPubMedCentral

Panaccione R, D’Haens G, Sandborn W, Ghosh S, Schreiber S, Tanida S, et al. Efficacy of upadacitinib as an induction therapy for patients with moderately to severely active ulcerative colitis, with or without previous treatment failure of biologic therapy: data from the dose-ranging phase 2B study U-Achieve [abstract no. 799]. Gastroenterology. 2019;156(6):S-170.CrossRef

10.

Sandborn W, Feagan B, Panes J, D’Haens G, Colombel JF, Zhou Q, et al. Safety and efficacy of ABT-494 (upadacitinib), an oral Jak1 inhibitor, as induction therapy in patients with Crohn’s disease: results from Celest. Gastroenterology. 2017;152(5):S1308–9. https://doi.org/10.1016/S0016-5085(17)34357-3.CrossRef

11.

Parmentier JM, Voss J, Graff C, Schwartz A, Argiriadi M, Friedman M, et al. In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494). BMC Rheumatol. 2018;2:23. https://doi.org/10.1186/s41927-018-0031-x.CrossRefPubMedPubMedCentral

12.

Mohamed MF, Camp HS, Jiang P, Padley RJ, Asatryan A, Othman AA. Pharmacokinetics, safety and tolerability of ABT-494, a novel selective JAK 1 inhibitor, in healthy volunteers and subjects with rheumatoid arthritis. Clin Pharmacokinet. 2016;55(12):1547–58. https://doi.org/10.1007/s40262-016-0419-y.CrossRefPubMed

13.

Kremer JM, Emery P, Camp HS, Friedman A, Wang L, Othman AA, et al. A phase IIb study of ABT-494, a selective JAK-1 inhibitor, in patients with rheumatoid arthritis and an inadequate response to anti-tumor necrosis factor therapy. Arthritis Rheumatol. 2016;68(12):2867–77. https://doi.org/10.1002/art.39801.CrossRefPubMedPubMedCentral

14.

Genovese MC, Smolen JS, Weinblatt ME, Burmester GR, Meerwein S, Camp HS, et al. Efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in a phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Rheumatol. 2016;68(12):2857–66. https://doi.org/10.1002/art.39808.CrossRefPubMedPubMedCentral

15.

Tanaka Y, Takeuchi T, Yamaoka K, Oribe M, Kawano M, Zhou Y, Othman AA, Pangan AL, Kitamura S, Matsuda N, Meerwein S. Kameda H. SAT0257 A phase 2b/3 randomised, placebo-controlled, double-blind study of upadacitinib, a selective jak1 inhibitor, in japanese patients with active rheumatoid arthritis and inadequate response to conventional synthetic DMARDs. Ann Rheum Dis. 2018;77(Suppl 2):991–2.

16.

Fleischmann R, Pangan AL, Song IH, Mysler E, Bessette L, Peterfy C, et al. Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase III, double-blind, randomized controlled trial. Arthritis Rheumatol. 2019;71(11):1788–800. https://doi.org/10.1002/art.41032.CrossRefPubMed

17.

Smolen JS, Pangan AL, Emery P, Rigby W, Tanaka Y, Vargas JI, et al. Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study. Lancet. 2019;393(10188):2303–11. https://doi.org/10.1016/S0140-6736(19)30419-2.CrossRefPubMed

18.

Burmester GR, Kremer JM, Van den Bosch F, Kivitz A, Bessette L, Li Y, et al. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10139):2503–12. https://doi.org/10.1016/S0140-6736(18)31115-2.CrossRefPubMed

19.

Genovese MC, Fleischmann R, Combe B, Hall S, Rubbert-Roth A, Zhang Y, et al. Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial. Lancet. 2018;391(10139):2513–24. https://doi.org/10.1016/S0140-6736(18)31116-4.CrossRefPubMed

20.

Van Vollenhoven R, Pangan AL, Friedman A, Mohamed MF, Chen S, Rischmueller M, et al. A phase 3, randomized, controlled trial comparing upadacitinib monotherapy to MTX monotherapy in MTX-naïve patients with active rheumatoid arthritis [abstract no. 891]. Arthritis Rheumatol. 2018;70(suppl 10).

21.

Sandborn W, Ghosh S, Panes J, et al. Efficacy and safety of upadacitinib as an induction therapy for patients with moderately-to-severely active ulcerative colitis: data from the phase 2b study u-achieve [oral presentation no. 195]. United European Gastroenterology Week; 20–24 Oct 2018; Vienna.

22.

Mohamed MF, Trueman S, Othman AA, Han JH, Ju TR, Marroum P. Development of in vitro-in vivo correlation for upadacitinib extended-release tablet formulation. AAPS J. 2019;21(6):108.CrossRef

23.

AbbVie Inc. RINVOQ™ (upadacitinib extended-release tablets) [US package insert]. North Chicago: AbbVie Inc.; 2019.

24.

AbbVie Inc. A study to evaluate the pharmacokinetics, safety, tolerability of upadacitinib in pediatric subjects with polyarticular course juvenile idiopathic arthritis [ClinicalTrials.gov identifier NCT03725007]. National Institutes of Health, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/nct03725007. Accessed 4 Nov 2019.

25.

Mohamed MF, Zeng J, Marroum PJ, Song IH, Othman AA. Pharmacokinetics of upadacitinib with the clinical regimens of the extended-release formulation utilized in rheumatoid arthritis phase 3 trials. Clin Pharmacol Drug Dev. 2019;8(2):208–16. https://doi.org/10.1002/cpdd.462.CrossRefPubMed

26.

Klunder B, Mohamed MF, Othman AA. Population pharmacokinetics of upadacitinib in healthy subjects and subjects with rheumatoid arthritis: analyses of phase I and II clinical trials. Clin Pharmacokinet. 2018;57(8):977–88. https://doi.org/10.1007/s40262-017-0605-6.CrossRefPubMed

27.

Klunder B, Mittapalli RK, Mohamed MF, Friedel A, Noertersheuser P, Othman AA. Population pharmacokinetics of upadacitinib using the immediate-release and extended-release formulations in healthy subjects and subjects with rheumatoid arthritis: analyses of phase I-III clinical trials. Clin Pharmacokinet. 2019;58(8):1045–58. https://doi.org/10.1007/s40262-019-00739-3.CrossRefPubMedPubMedCentral

28.

Mohamed MF, Camp HS, Jungerwirth S, Othman AA. Pharmacokinetics of upadacitinib in healthy Japanese and Chinese subjects and comparability to western subjects [abstract]. Clin Pharmacol Ther. 2018;103(S1):S80.

29.

Mohamed MF, Klunder B, Meerwein S, Othman A. Upadacitinib pharmacokinetics in Japanese subjects with rheumatoid arthritis with the extended release formulation and comparability to non-Japanese subjects [poster no. THU0183]. Ann Rheum Dis. 2019;78:367.

30.

Trueman S, Mohamed MF, Feng T, Lacerda AP, Marbury T, Othman AA. Characterization of the effect of hepatic impairment on upadacitinib pharmacokinetics. J Clin Pharmacol. 2019;59(9):1188–94. https://doi.org/10.1002/jcph.1414.CrossRefPubMedPubMedCentral

31.

Mohamed MF, Trueman S, Feng T, Anderson J, Marbury TC, Othman AA. Characterization of the effect of renal impairment on upadacitinib pharmacokinetics. J Clin Pharmacol. 2019;59(6):856–62. https://doi.org/10.1002/jcph.1375.CrossRefPubMedPubMedCentral

32.

Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461–70. https://doi.org/10.7326/0003-4819-130-6-199903160-00002.

33.

Mohamed MF, Jungerwirth S, Asatryan A, Jiang P, Othman AA. 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):2242–8. https://doi.org/10.1111/bcp.13329.CrossRefPubMedPubMedCentral

34.

Mohamed MF, Coppola S, Feng T, Camp H, Othman AA. Lack of clinically- relevant effect of upadacitinib on plasma exposures of rosuvastatin and atorvastatin. Clin Pharmacol Drug Dev. 2019; 8(S1)

35.

U.S. Department of Health and Human Services. Guidance for industry: Clinical drug interaction studies—study design, data analysis, and clinical implications. October 2017. https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf. Accessed 6 Nov 2019

36.

Mohamed MF, Feng T, Enejosa JV, Fisniku O, Othman AA. Effects of upadacitinib coadministration on the pharmacokinetics of sensitive cytochrome P450 probe substrates: a study with the Modified Cooperstown 5 + 1 Cocktail. J Clin Pharmacol. 2019. https://doi.org/10.1002/jcph.1496(epub 2019 Aug 5).CrossRefPubMedPubMedCentral

37.

EMA. Guideline on the investigation of drug interactions. London: European Medicines Agency (EMA); 2012. p. 1–59.

38.

Minocha M, Trueman S, Mohamed M-EF, Feng T, Enejosa J, Othman AA. Chronic dosing of upadacitinib, an oral selective JAK-1 inhibitor, does not impact exposures of bupropion, a probe substrate for cytochrome P450 2B6 metabolism. Clin Pharmacol Ther. 2019;105(Suppl 1):S63.

39.

Zhang H, Cui D, Wang B, Han YH, Balimane P, Yang Z, et al. Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol: a new look at an old drug. Clin Pharmacokinet. 2007;46(2):133–57. https://doi.org/10.2165/00003088-200746020-00003.CrossRefPubMed

40.

Mohamed MF, Trueman S, Feng T, Friedman A, Othman AA. The JAK1 inhibitor upadacitinib has no effect on the pharmacokinetics of levonorgestrel and ethinylestradiol: a study in healthy female subjects. J Clin Pharmacol. 2019;59(4):510–6. https://doi.org/10.1002/jcph.1350.CrossRefPubMed

Title: Clinical Pharmacokinetics of Upadacitinib: Review of Data Relevant to the Rheumatoid Arthritis Indication
Authors: Mohamed-Eslam F. Mohamed
Ben Klünder
Ahmed A. Othman
Publication date: 01-05-2020
Publisher: Springer International Publishing
Keywords: Pharmacokinetics
Methotrexate
Methotrexate
Rheumatoid Arthritis
Published in: Clinical Pharmacokinetics / Issue 5/2020
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-019-00855-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Clinical Pharmacokinetics of Upadacitinib: Review of Data Relevant to the Rheumatoid Arthritis Indication

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2020

A Population Pharmacokinetic Model Does Not Predict the Optimal Starting Dose of Tacrolimus in Pediatric Renal Transplant Recipients in a Prospective Study: Lessons Learned and Model Improvement

Fetal Physiologically Based Pharmacokinetic Models: Systems Information on Fetal Blood Components and Binding Proteins

Pharmacokinetics and Pharmacodynamics of Approved and Investigational P2Y12 Receptor Antagonists

Comment on “Levothyrox® New and Old Formulations: Are They Switchable for Millions of Patients?”

Clinical Pharmacokinetics and Pharmacodynamics of Imipenem–Cilastatin/Relebactam Combination Therapy

Favorable Pharmacokinetic Characteristics of Extended-Half-Life Recombinant Factor VIII BAY 94-9027 Enable Robust Individual Profiling Using a Population Pharmacokinetic Approach