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Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase that is used in the therapy of refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma.  Ibrutinib has not been associated with serum enzyme elevations during therapy and has yet to be linked to cases of clinically apparent acute liver injury.



Ibrutinib (eye broo’ ti nib) is an orally available, small molecule inhibitor of Bruton’s tyrosine kinase (BTK), which is an essential component in the B cell receptor signaling pathway. Inhibition of this pathway prevents B cell activation, differentiation and proliferation.  Deficiency of BTK is the cause of X linked (Bruton’s) agammaglobulinemia, and B cell receptor signaling through BTK has been shown to be critical for proliferation and survival of malignant B lymphocytes in mantle cell lymphoma and CLL.  Ibrutinib was approved for use in the United States as therapy for refractory mantle cell lymphoma in 2013 and for refractory CLL in 2014.  Ibrutinib is available in capsules of 140 mg under the brand name Imbruvica.  The recommended dose is 420 (CLL) or 540 (lymphoma) mg orally, once daily.  Side effects are common, but usually mild-to-moderate in severity; they include myelosuppression, fatigue, diarrhea, nausea, vomiting, anorexia, constipation, peripheral edema, dyspnea, arthralgia, myalgia, rash and fever.  Uncommon, but potentially serious side effects include severe bone marrow suppression, infections, bleeding and renal toxicity.



In clinical trials of ibrutinib in patients with CLL and mantle cell lymphoma, the rates of serum enzyme elevations during therapy were not reported and there were no reported instances of clinically apparent liver injury or need for early discontinuation because of hepatotoxicity.  The toxicities of ibrutinib resemble those of the tyrosine kinase receptor inhibitors.  While ibrutinib depresses peripheral lymphocyte counts and can cause neutropenia, it has little effect on serum immunoglobulin levels and has not been linked to instances of reactivation of opportunistic infections or hepatitis B or exacerbations of chronic hepatitis C (however, hepatitis B and C were exclusion criteria in most prelicensure studies).  Ibrutinib is metabolized in the liver via the cytochrome P450 system, largely CYP 3A4 and is susceptible to drug-drug interactions with agents that inhibit or induce this enzyme reactivity.  The absence of reports of hepatotoxicity from ibrutinib may relate to its relatively limited use.


Drug Class:  Antineoplastic Agents, Protein Kinase Inhibitors


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Ibrutinib – Imbruvica®


Antineoplastic Agents



Product labeling at DailyMed, National Library of Medicine, NIH


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Ibrutinib 936563-96-1 C25-H24-N6-O2 Ibrutinib chemical structure

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References updated: 14 July 2014

  1. Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.  (Review of hepatotoxicity published in 1999 before the availability of tyrosine kinase receptor inhibitors).

  2. DeLeve LD. Kinase inhibitors. Gefitinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 556.  (Review of hepatotoxicity of cancer chemotherapeutic agents, does not discuss ibrutinib).

  3. Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.  (Textbook of pharmacology and therapeutics).

  4. Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, Keating MJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 2012; 119: 1182-9. PubMed Citation  (Preclinical study of the activity of ibrutinib in inhibiting BTK and its effects on malignant B cells in vitro and in mouse models of CLL).

  5. Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, Kolibaba KS, 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: 88-94. PubMed Citation  (Among 56 patients with various B cell malignancies treated with escalating doses of ibrutinib, the overall objective response rate was 54%, with highest rates in CLL and mantle cell lymphoma; side effects included diarrhea, nausea, anorexia and fatigue, and no mention of ALT elevations or hepatotoxicity).

  6. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013; 369: 507-16. PubMed Citation  (Among 111 patients with refractory mantle cell lymphoma treated with ibrutinib for 1-24 months, the objective response rate was 68% [complete in 21%]; listing of side effects does not include ALT elevations or hepatotoxicity).

  7. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013; 369: 32-42. PubMed Citation  (Among 85 patients with refractory CLL treated with ibrutinib as a single agent, the overall response rate was 71%; side effects included diarrhea [49%], fatigue [32%], cough [31%], arthralgias [27%], rash [27%], fever [27%], peripheral edema [21%] and hypertension [18%]; ALT elevations and hepatotoxicity were not listed or mentioned).

  8. O'Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, Grant B, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol 2014; 15: 48-58. PubMed Citation  (Among 31 patients 65 years or older with CLL who were treated with ibrutinib, side effects were similar in frequency and severity to those reported in younger patients; no mention of hepatotoxicity or ALT elevations).

  9. Ponader S, Burger JA. Bruton's tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies. J Clin Oncol 2014; 32: 1830-9. PubMed Citation  (History of discovery of X-linked agammaglobulinemia, identification of BTK as its cause, elucidation of role of BTK in the pathway of B cell activation, and development of BTK inhibitors including ibrutinib).

  10. Bhatt V, Alejandro L, Michael A, Ganetsky A. The promising impact of ibrutinib, a Bruton's tyrosine kinase inhibitor, for the management of lymphoid malignancies. Pharmacotherapy 2014; 34: 303-14. PubMed Citation  (Review of pharmacology, efficacy and safety of ibrutinib; in discussion of its many side effects, there is no mention of ALT elevations or hepatotoxicity).

  11. Ibrutinib (Imbruvica) for chronic lymphocytic leukemia. Med Lett Drugs Ther 2014; 56 (1440): 29-30. PubMed Citation  (Concise review of mechanism of action, efficacy, safety and cost of ibrutinib shortly after its approval for use in the US, mentions that serious adverse events include cytopenias, bleeding and infections; no mention of ALT elevations or hepatotoxicity).

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  1. PubMed logoRecent References on Ibrutinib

  2. Clinical Trials logoTrials on Ibrutinib

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