Clinical pharmacology and PK/PD translation of the second-generation Bruton’s tyrosine kinase inhibitor, zanubrutinib

References

• Dal Porto JM, Gauld SB, Merrell KT, et al. B cell antigen receptor signaling 101. Mol Immunol. 2004;41(6–7):599–613.
   PubMed Web of Science ®Google Scholar
• Niiro H, Clark EA. Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol. 2002;2(12):945–956.
   PubMed Web of Science ®Google Scholar
• Rickert RC. New insights into pre-BCR and BCR signalling with relevance to B cell malignancies. Nat Rev Immunol. 2013;13(8):578–591.
   PubMed Web of Science ®Google Scholar
• Niemann CU, Wiestner A. B-cell receptor signaling as a driver of lymphoma development and evolution. Semin Cancer Biol. 2013;23(6):410–421.
   PubMed Web of Science ®Google Scholar
• Xu W, Song Y, Li Z, et al. Safety, tolerability and efficacy of orelabrutinib, once a day, to treat Chinese patients with relapsed or refractory chronic lymphocytic leukemia/small cell leukemia. Blood. 2019;134(Suppl_1):4319.
   Google Scholar
• Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892–901.
   PubMed Web of Science ®Google Scholar
• Song Y, Zhou K, Zou D, et al. Treatment of patients with relapsed or refractory mantle-cell lymphoma with zanubrutinib, a selective inhibitor of Bruton’s tyrosine kinase. Clin Cancer Res. 2020;26(16): 4216–4224.
   PubMed Web of Science ®Google Scholar
• Tam CS, Opat S, Simpson D, et al. Zanubrutiib for the treatment of relapsed or refractory mantle cell lymphoma. Blood Adv. 2021;5(12):2577–2585.
   PubMed Web of Science ®Google Scholar
• Brukinsa® [package insert]. Beijing China: BeiGene Co. Ltd; 2019 November.
   Google Scholar
• BeiGene Press Release. BeiGene announces the approval of BRUKINSATM (Zanubrutinib) in China for patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed/refractory mantle cell lymphoma 2020. [cited 2021 Aug 1]. Available from: http://ir.beigene.com/news-releases/news-release-details/beigene-announces-approval-brukinsatm-zanubrutinib-china]
   Google Scholar
• Tam CSL, Trotman J, Opat S, et al. Phase 1 study of selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019;134(11):851–859.
   PubMed Web of Science ®Google Scholar
• Xu W, Yang S, Zhou K, et al. Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with the BTK inhibitor zanubrutinib: phase 2, single-arm, multicenter study. J Hematol Oncol. 2020;13(1):48.
   PubMed Web of Science ®Google Scholar
• BeiGene Press release. Health Canada approves brukinsa® (zanubrutinib) for the treatment of waldenstrom’s macroglobulinemia. 2021. [cited 2021 Aug 1]. Available from https://ir.beigene.com/news-releases/news-release-details/health-canada-approves-brukinsar-zanubrutinib-treatment].
   Google Scholar
• Hillmen P, Eichhorst B, Brown JR, et al. First interim analysis of ALPINE study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. EHA 2021. LB 1900.
   Google Scholar
• US Food and Drug Administration Center for Drug Evaluation and Research (Ibrutinib ImbruvicaTM). Application number 20552Orig2s000. [cited 2021 Aug 1]. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205552Orig2s000ClinPharmR.pdf]
   Google Scholar
• Herman SE, Mustafa RZ, Gyamfi JA, et al. Ibrutinib inhibits BCR and NF-kappa B signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood. 2014;123(21):3286–3295.
   PubMed Web of Science ®Google Scholar
• Imbruvica® (ibrutinib) [package insert]. Sunnyvale Ca: Pharmacyclics, LLC; 2015.
   Google Scholar
• Guo Y, Liu Y, Hu NY, et al., Discovery of zanubrutinib (BGB-3111), a novel, potent, and selective covalent inhibitor of Bruton’s tyrosine kinase. J Med Chem. 62(17): 7923–7940. 2019.
   PubMed Web of Science ®Google Scholar
• Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363(2):240–252.
   PubMed Web of Science ®Google Scholar
• Kohrt HE, Sagiv-Barfi I, Rafiq S, et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood. 2014;123(12):1957–1960.
   PubMed Web of Science ®Google Scholar
• Burger JA, Sivina M, Jain N, et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2018;133(10):1011–1019.
   PubMed Web of Science ®Google Scholar
• Woyach J, Ruppert AS, Perez G, et al. Alliance A041702: a randomized phase III study of ibrutinib plus obinutuzumab versus ibrutinib plus venetoclax and obinutuzumab in untreated older patients (≥ 70 years of age) with chronic lymphocytic leukemia (CLL). Blood. 2019;134(Supplement_1):1751.
   Google Scholar
• Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432–443.
   PubMed Web of Science ®Google Scholar
• Kaptein A, De Bruin G, Emmelot-van Hoek M, et al. Potency and selectivity of BTK inhibitors in clinical development for B-Cell malignancies. Blood. 2018;132(Supplement 1):1871.
   PubMedGoogle Scholar
• Wang K, Yao X, Zhang M, et al. Comprehensive PBPK model to predict drug interaction potential of zanubrutinib as a victim or perpetrator. CPT Pharmacometrics Syst Pharmacol. 2021;10(5):441–454. epub ahead of print.
   Google Scholar
• De Vries R, Smit JW, Hellemans P, et al. Stable isotope-labelled intravenous microdose for absolute bioavailability and effect of grapefruit juice on ibrutinib in healthy adults. Br J Clin Pharmacol. 2016;81(2):235–245.
   PubMed Web of Science ®Google Scholar
• Canada H. Brukinsa®Product Monograph. Canada; BeiGene, 2021.
   Google Scholar
• Calquence® [package insert]. AstraZeneca Gaithersburg MD. November 2019.
   Google Scholar
• Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323–332.
   PubMed Web of Science ®Google Scholar
• Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88–94.
   PubMed Web of Science ®Google Scholar
• DImopoulos M, Opat S, Lee H-P, et al. Major responses in MYD88 wildtype (MYD88WT) Waldenstrom macroglobulinemia (WM) patients treated with Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (BGB-3111) 2019 [cited 2021 Aug 1]. Available from: https://library.ehaweb.org/eha/2019/24th/266287/meletios.a.dimopoulos.major.responses.in.myd88.wildtype.%28myd88wt%29.waldenstrm.html].
   Google Scholar
• Alsadhan A, Cheung J, Gulrajani M, et al. Pharmacodynamic analysis of BTK inhibition in patients with chronic lymphocytic leukemia treated with acalabrutinib. Clin Cancer Res. 2020;26(12):2800–2809.
   PubMed Web of Science ®Google Scholar
• Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42. 69.
   PubMed Web of Science ®Google Scholar
• Sun C, Nierman P, Kendall EK, et al. Clinical and biological implications of target occupancy in CLL treated with the BTK inhibitor acalabrutinib. Blood. 2020;136(1):93–105.
   PubMed Web of Science ®Google Scholar
• Moreau P, Mateos MV, Berenson JR, et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 2018;19(7):953–964.
   PubMed Web of Science ®Google Scholar
• Saffran DC, Parolini O, Fitch-Hilgenberg ME, et al. A point mutation in the SH2 domain of Bruton’s tyrosine kinase in atypical X-linked agammaglobulinemia. N Engl J Med. 1994;330(21):1488–1491.
   PubMed Web of Science ®Google Scholar
• US Food and Drug Administration Center for Drug Evaluation and Research. Application number 213217Orig1s00 multi-discipline review package. 2019 [ Bruinksa] [cited 2021 Aug 1]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/213217Orig1s000MultidisciplineR.pdf].
   Google Scholar
• de Jong J, Sukbuntherng J, Skee D, et al. The effect of food on the pharmacokinetics of oral ibrutinib in healthy participants and patients with chronic lymphocytic leukemia. Cancer Chemother Pharmacol. 2015;75(5):907–916.
   PubMed Web of Science ®Google Scholar
• US Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number 210259Orig1S006, 210259Orig1s007 (CALQUENCE capsules). [cited 2021 Aug 1]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/210259Orig1s006,%20s007.pdf].
   Google Scholar
• Podoll T, Pearson PG, Evarts J, et al. Bioavailability, biotransformation, and excretion of the covalent Bruton tyrosine kinase inhibitor acalabrutinib in rats, dogs, and humans. Drug Metab Dispos. 2019;47(2):145–154.
   PubMed Web of Science ®Google Scholar
• Scheers E, Leclercq L, de Jong J, et al. Absorption, metabolism, and excretion of oral (1)(4)C radiolabeled ibrutinib: an open-label, phase I, single-dose study in healthy men. Drug Metab Dispos. 2015;43(2):289–297.
   PubMed Web of Science ®Google Scholar
• Wong J, Cher L, Griffiths J, et al. Efficacy of zanubrutinib in the treatment of bing-neel syndrome. Hemasphere. 2018;2(6):e155.
   PubMed Web of Science ®Google Scholar
• Goldwirt L, Beccaria K, Ple A, et al. Ibrutinib brain distribution: a preclinical study. Cancer Chemother Pharmacol. 2018;81(4):783–789.
   PubMed Web of Science ®Google Scholar
• Bernard S, Goldwirt L, Amorim S, et al. Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse. Blood. 2015;126(14):1695–1698.
   PubMed Web of Science ®Google Scholar
• Ou YC, Liu L, Tariq B, et al. Population pharmacokinetic analysis of the BTK inhibitor zanubrutinib in healthy volunteers and patients with B-Cell malignancies. Clin Transl Sci. 2021;14(20):764–772.
   PubMedGoogle Scholar
• Ou YC, Preston RA, Marbury TC, et al. A phase 1, open-label, single-dose study of the pharmacokinetics of zanubrutinib in subjects with varying degrees of hepatic impairment. Leuk Lymphoma. 2020;61(6):1355–1363.
   PubMed Web of Science ®Google Scholar
• Mu S O, Tang Z, Novotny W, et al. Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton’s tyrosine kinase inhibitor) in Asian and non-Asian healthy subjects. Cancer Chemother Pharmacol. 2020;85(2):391–399.
   PubMed Web of Science ®Google Scholar
• Marostica E, Sukbuntherng J, Loury D, et al. Population pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies. Cancer Chemother Pharmacol. 2015;75(1):111–121.
   PubMed Web of Science ®Google Scholar
• Edlund H, Lee SK, Andrew MA, et al. Population pharmacokinetics of the BTK inhibitor acalabrutinib and its active metabolite in healthy volunteers and patients with B-cell malignancies. Clin Pharmacokinet. 2019;58(5):659–672.
   PubMed Web of Science ®Google Scholar
• Bruggemann RJ, Alffenaar JW, Blijlevens NM, et al. Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis. 2009;48(10):1441–1458.
   PubMed Web of Science ®Google Scholar
• de Jong J, Skee D, Murphy J, et al. Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants. Pharmacol Res Perspect. 2015;3(4):e00156.
   PubMed Web of Science ®Google Scholar
• Finnes HD, Chaffee KG, Call TG, et al. Pharmacovigilance during ibrutinib therapy for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in routine clinical practice. Leuk Lymphoma. 2017;58(6):1376–1383.
   PubMed Web of Science ®Google Scholar
• Barr PM, Brown JR, Hillmen P, et al. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood. 2017;129(19):2612–2615.
   PubMed Web of Science ®Google Scholar
• de Jong J, Hellemans P, Jiao J, et al. An open-label, sequential-design drug interaction study of the effects of omeprazole on the pharmacokinetics of ibrutinib in healthy adults. Blood. 2016;128(22):1588.
   Web of Science ®Google Scholar
• Budha NR, Frymoyer A, Smelick GS, et al. Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? Clin Pharmacol Ther. 2012;92(2):203–213.
   PubMed Web of Science ®Google Scholar
• Ou YC, Tang Z, Novotny W, et al. Evaluation of drug interaction potential of zanubrutinib with cocktail probes representative of CYP3A4, CYP2C9, CYP2C19, P-gp and BCRP. Br J Clin Pharmacol. 2021;87(7):2926–2936.
   Web of Science ®Google Scholar
• Zhou D, Podoll T, Xu Y, et al. Evaluation of the drug-drug interaction potential of acalabrutinib and Its active metabolite, ACP-5862, using a physiologically-based pharmacokinetic modeling approach. CPT Pharmacometrics Syst Pharmacol. 2019;8(7):489–499.
   PubMedGoogle Scholar
• Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib versus ibrutinib in symptomatic Waldenstrom macroglobulinemia: the Aspen study. Blood. 2020136(18):2038–2050.
   PubMed Web of Science ®Google Scholar
• de Jong J, Hellemans P, Jiao JJ, et al. Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study. Cancer Chemother Pharmacol. 2017;80(6):1227–1237.
   PubMed Web of Science ®Google Scholar
• Mu S, Darpo B, Tang Z, et al. No QTc prolongation with zanubrutinib: results of concentration-QTc analysis from a thorough QT study in healthy subjects. Clin Transl Sci. 2020;13(5):923–931.
   PubMed Web of Science ®Google Scholar
• Kamel S, Horton L, Ysebaert L, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia. 2015;29(4):783–787.
   PubMed Web of Science ®Google Scholar
• Levade M, David E, Garcia C, et al. Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions. Blood. 2014;124(26):3991–3995.
   PubMed Web of Science ®Google Scholar
• Tam CS, Opat S, Zhu J, et al. Pooled analysis of safety data from monotherapy studies of the Bruton tyrosine kinase (BTK) inhibitor, zanubrutinib (BGB-3111) in B-cell malignancies. 24th European Hematology Association Congress; June 13–16, 2019; Amsterdam, The Netherlands 2019.
   Google Scholar
• Tang CPS, McMullen J, Tam C. Cardiac side effects of bruton tyrosine kinase (BTK) inhibitors. Leuk Lymphoma. 2018;59(7):1554–1564.
   PubMed Web of Science ®Google Scholar
• Estupiñán YH, Berglöf A, Zain R, et al. Comparative analysis of BTK inhibitors and mechanisms underlying adverse effects. Front Cell Dev Biol. 2021;9:630942.
   PubMed Web of Science ®Google Scholar
• Farrar JE, Rohrer J, Conley ME. Neutropenia in X-linked agammaglobulinemia. Clin Immunol Immunopathol. 1996;81(3):271–276.
   PubMedGoogle Scholar
• Ou YC, Tang Z, Novotny W, et al. Rationale for once-daily or twice-daily dosing of zanubrutinib in patients with mantle cell lymphoma. Leuk Lymphoma. 2021;1–13. epub ahead of print. https://doi.org/10.1080/10428194.2021.1929961.
   Google Scholar
• Atkinson BT, Ellmeier W, Watson SP. Tec regulates platelet activation by GPVI in the absence of Btk. Blood. 2003;102(10):3592–3599.
   PubMed Web of Science ®Google Scholar
• Quek LS, Bolen J, Watson SP. A role for Bruton’s tyrosine kinase (Btk) in platelet activation by collagen. Curr Biol. 1998;8(20):1137–1140.
   PubMed Web of Science ®Google Scholar
• Rigg RA, Aslan JE, Healy LD, et al. Oral administration of Bruton’s tyrosine kinase inhibitors impairs GPVI-mediated platelet function. Am J Physiol Cell Physiol. 2016;310(5):C373–80.
   PubMed Web of Science ®Google Scholar
• Shatzel JJ, Olson SR, Tao DL, et al. Ibrutinib-associated bleeding: pathogenesis, management and risk reduction strategies. J Thromb Haemost. 2017;15(5):835–847.
   PubMed Web of Science ®Google Scholar
• Bye AP, Unsworth AJ, Desborough MJ, et al. Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib. Blood Adv. 2017;1(26):2610–2623.
   PubMed Web of Science ®Google Scholar
• Tam CS, LeBlond V, Novotny W, et al. A head-to-head Phase III study comparing zanubrutinib versus ibrutinib in patients with Waldenstrom macroglobulinemia. Future Oncol. 2018;14(22):2229–2237.
   PubMed Web of Science ®Google Scholar
• Bye AP, Unsworth AJ, Vaiyapuri S, et al. Ibrutinib inhibits platelet integrin αIIbβ3 outside-in signaling and thrombus stability but not adhesion to collagen. Arterioscler Thromb Vasc Biol. 2015;35(11):2326–2335.
   PubMed Web of Science ®Google Scholar
• Dobie G, Kuriri FA, Omar MMA, et al., Ibrutinib, but not zanubrutinib, induces platelet receptor shedding of GPIb-IX-V complex and integrin αIIbβ3 in mice and humans. Blood Adv. 2019;3(24):4298–4311.
   PubMed Web of Science ®Google Scholar
• McMullen JR, Boey EJ, Ooi JY, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124(25):3829–3830.
   PubMed Web of Science ®Google Scholar
• Pretorius L, Du XJ, Woodcock EA, et al. Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation. Am J Pathol. 2009;175(3):998–1009.
   PubMed Web of Science ®Google Scholar
• Xiao L, Salem JE, Clauss S, et al. Ibrutinib-mediated atrial fibrillation attributable to inhibition of C-terminal Src kinase. Circulation. 2020;142(25):2443–2455.
   PubMed Web of Science ®Google Scholar
• Berglof A, Hamasy A, Meinke S, et al. Targets for ibrutinib beyond B cell malignancies. Scand J Immunol. 2015;82(3):208–217.
   PubMed Web of Science ®Google Scholar
• Zou YX, Zhu HY, Li XT, et al. The impacts of zanubrutinib on immune cells in patients with chronic lymphocytic leukemica/small lymphocytic lymphoma. Hematol Oncol. 2019;37(4):392–400.
   PubMed Web of Science ®Google Scholar
• Choy EH. Clinical significance of Janus kinase inhibitor selectivity. Rheumatology (Oxford). 2019;58(6):953–962.
   PubMed Web of Science ®Google Scholar
• Tam CS, Wang M, SImpson D, et al. Updated safety and efficacy data in the phase 1 trial of patients with mantle cell lymphoma (MCL) treated with Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (BGB-3111). Hematol Oncol. 2019;37:245–247.
   Google Scholar
• Trotman J, Opat S, Gottlieb D, et al. Zanubrutinib for the treatment of patients with waldenstrom macroglobulinemia: 3 years of follow-up. Blood. 2020;136(18):2027–2037.
   PubMed Web of Science ®Google Scholar