Skip to main content

Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Chronic Lymphocytic Leukemia: Ibrutinib, Idelalisib, and Venetoclax

Clinical Pharmacokinetics volume 56, pages 1255–1266 (2017)Cite this article

Abstract

Management of chronic lymphocytic leukemia has changed markedly over the last several years with the emergence of several novel oral agents targeting B-cell receptor and Bcl-2 signaling pathways. For patients requiring treatment, ibrutinib, idelalisib, and venetoclax offer unique clinical benefits with a different set of therapeutic considerations compared with traditional parenteral therapy. Despite the conveniences afforded by oral therapy, these agents also carry unique logistical obstacles. Drug interactions with agents that are metabolized via the cytochrome P450 3A4 pathway are possible with all three agents. Unique treatment-related adverse events including bleeding and atrial fibrillation with ibrutinib, hepatotoxicity with idelalisib, and tumor lysis syndrome with venetoclax can be severe and dose limiting. Furthermore, dose adjustments for organ dysfunction may also be warranted. Here, we review the available literature on the pharmacokinetic and pharmacodynamic properties of these novel agents to guide the reader in the appropriate use of ibrutinib, idelalisib, and venetoclax.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

49,54 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164–74. doi:10.1016/S0140-6736(10)61381-5.

    CAS  Article  PubMed  Google Scholar 

  2. Robak T, Dmoszynska A, Solal-Celigny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2010;28(10):1756–65. doi:10.1200/JCO.2009.26.4556.

    CAS  Article  PubMed  Google Scholar 

  3. Hillmen P, Gribben JG, Follows GA, et al. Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: final analysis of an open-label phase II study. J Clin Oncol. 2014;32(12):1236–41. doi:10.1200/JCO.2013.49.6547.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Foa R, Del Giudice I, Cuneo A, et al. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014;89(5):480–6. doi:10.1002/ajh.23668.

    CAS  Article  PubMed  Google Scholar 

  5. Coiffier B, Lepretre S, Pedersen LM, et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1–2 study. Blood. 2008;111(3):1094–100. doi:10.1182/blood-2007-09-111781.

    CAS  Article  PubMed  Google Scholar 

  6. Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010;28(10):1749–55. doi:10.1200/JCO.2009.25.3187.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101–10. doi:10.1056/NEJMoa1313984.

    CAS  Article  PubMed  Google Scholar 

  8. Wilson WH. Progress in chronic lymphocytic leukemia with targeted therapy. N Engl J Med. 2016;374(4):386–8. doi:10.1056/NEJMe1515235.

    Article  PubMed  Google Scholar 

  9. Markham A. Idelalisib: first global approval. Drugs. 2014;74(14):1701–7. doi:10.1007/s40265-014-0285-6.

    CAS  Article  PubMed  Google Scholar 

  10. Deeks ED. Venetoclax: first global approval. Drugs. 2016;76(9):979–87. doi:10.1007/s40265-016-0596-x.

    CAS  Article  PubMed  Google Scholar 

  11. Cameron F, Sanford M. Ibrutinib: first global approval. Drugs. 2014;74(2):263–71. doi:10.1007/s40265-014-0178-8.

    CAS  Article  PubMed  Google Scholar 

  12. Given BA, Spoelstra SL, Grant M. The challenges of oral agents as antineoplastic treatments. Semin Oncol Nurs. 2011;27(2):93–103. doi:10.1016/j.soncn.2011.02.003.

    Article  PubMed  Google Scholar 

  13. DeMario MD, Ratain MJ. Oral chemotherapy: rationale and future directions. J Clin Oncol. 1998;16(7):2557–67.

    CAS  Article  PubMed  Google Scholar 

  14. 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. doi:10.1200/JCO.2012.42.7906.

    CAS  Article  PubMed  Google Scholar 

  15. Bernal A, Pastore RD, Asgary Z, et al. Survival of leukemic B cells promoted by engagement of the antigen receptor. Blood. 2001;98(10):3050–7.

    CAS  Article  PubMed  Google Scholar 

  16. Craxton A, Jiang A, Kurosaki T, Clark EA. Syk and Bruton’s tyrosine kinase are required for B cell antigen receptor-mediated activation of the kinase Akt. J Biol Chem. 1999;274(43):30644–50.

    CAS  Article  PubMed  Google Scholar 

  17. 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. doi:10.1056/NEJMoa1215637.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Imbruvica [package insert] Janssen Biotech, Inc. Horsham, PA. 2017.

  19. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–23. doi:10.1056/NEJMoa1400376.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425–37. doi:10.1056/NEJMoa1509388.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17(2):200–11. doi:10.1016/S1470-2045(15)00465-9.

    CAS  Article  PubMed  Google Scholar 

  22. McMullen JR, Boey EJH, Ooi JYY, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124(25):3829–30. doi:10.1182/blood-2014-10-604272.

    CAS  Article  PubMed  Google Scholar 

  23. Herman SE, Niemann CU, Farooqui M, et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia. 2014;28(11):2188–96. doi:10.1038/leu.2014.122.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Herman SE, Mustafa RZ, Gyamfi JA, et al. Ibrutinib inhibits BCR and NF-kappaB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood. 2014;123(21):3286–95. doi:10.1182/blood-2014-02-548610.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 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):289–97. doi:10.1124/dmd.114.060061.

    Article  PubMed  Google Scholar 

  26. 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):235–45. doi:10.1111/bcp.12787.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kohrt HE, Sagiv-Barfi I, Rafiq S, et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood. 2014;123(12):1957–60. doi:10.1182/blood-2014-01-547869.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 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):111–21. doi:10.1007/s00280-014-2617-3.

    CAS  Article  PubMed  Google Scholar 

  29. de Jong J, Skee D, Hellemans P, et al. Single-dose pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment. Leuk Lymphoma. 2016;. doi:10.1080/10428194.2016.1189548.

    PubMed  Google Scholar 

  30. Shibata Y, Chiba M. The role of extrahepatic metabolism in the pharmacokinetics of the targeted covalent inhibitors afatinib, ibrutinib, and neratinib. Drug Metab Dispos. 2015;43(3):375–84. doi:10.1124/dmd.114.061424.

    Article  PubMed  Google Scholar 

  31. Lipsky AH, Farooqui MZ, Tian X, et al. Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib. Haematologica. 2015;100(12):1571–8. doi:10.3324/haematol.2015.126672.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Korycka-Wolowiec A, Wolowiec D, Robak T. Pharmacodynamic considerations of small molecule targeted therapy for treating B-cell malignancies in the elderly. Exp Opin Drug Metab Toxicol. 2015;11(9):1371–91. doi:10.1517/17425255.2015.1055246.

    CAS  Article  Google Scholar 

  33. Gopal AK, Kahl BS, de Vos S, et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008–18. doi:10.1056/NEJMoa1314583.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116(12):2078–88. doi:10.1182/blood-2010-02-271171.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Davies A. Idelalisib for relapsed/refractory indolent B-cell non-Hodgkin’s lymphoma: an overview of pharmacokinetics and clinical trial outcomes. Exp Rev Hematol. 2015;8(5):581–93. doi:10.1586/17474086.2015.1071663.

    CAS  Article  Google Scholar 

  36. Shah A, Mangaonkar A. Idelalisib: a novel PI3Kdelta inhibitor for chronic lymphocytic leukemia. Ann Pharmacother. 2015;49(10):1162–70. doi:10.1177/1060028015594813.

    CAS  Article  PubMed  Google Scholar 

  37. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997–1007. doi:10.1056/NEJMoa1315226.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390–7. doi:10.1182/blood-2013-11-535047.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Zydelig [package insert] Gilead Sciences, Inc. Foster, CA. 2016.

  40. Robeson M, Zhou H, Kwan E, Ramanathan S. Pharmacokinetics, metabolism and excretion of idelalisib. Blood. 2013;122(21):5570.

    Google Scholar 

  41. Webb HK, Chen H, Yu AS, et al. Clinical pharmacokinetics of CAL-101, a p110d isoform-selective PI3K inhibtor, following single- and multiple dose administration in healthy volunteers and patients with hematological malignancies. ASH Annual Meeting Abstracts. 2010;116(21):1774.

    Google Scholar 

  42. Jin F, Gao Y, Zhou H, et al. Population pharmacokinetic modeling of idelalisib, a novel PI3Kdelta inhibitor, in healthy subjects and patients with hematologic malignancies. Cancer Chemother Pharmacol. 2016;77(1):89–98. doi:10.1007/s00280-015-2891-8.

    CAS  Article  PubMed  Google Scholar 

  43. Winiarska M, Bojarczuk K, Pyrzynska B, Bil J, et al. Inhibitors of SRC kinases impair antitumor activity of anti-CD20 monoclonal antibodies. MAbs. 2014;6(5):1300–13. doi:10.4161/mabs.32106.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Bojarczuk K, Siernicka M, Dwojak M, et al. B-cell receptor pathway inhibitors affect CD20 levels and impair antitumor activity of anti-CD20 monoclonal antibodies. Leukemia. 2014;28(5):1163–7. doi:10.1038/leu.2014.12.

    CAS  Article  PubMed  Google Scholar 

  45. Zelenetz AD, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib monotherapy in previously untreated patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Blood. 2014;124(21):1986.

    Google Scholar 

  46. Lampson BL, Kasar SN, Matos TR, et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood. 2016;128(2):195–203. doi:10.1182/blood-2016-03-707133.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Jin F, Robeson M, Zhou H, et al. Clinical drug interaction profile of idelalisib in healthy subjects. J Clin Pharmacol. 2015;55(8):909–19. doi:10.1002/jcph.495.

    CAS  Article  PubMed  Google Scholar 

  48. Jin F, Robeson M, Zhou H, et al. The pharmacokinetics and safety of idelalisib in subjects with moderate or severe hepatic impairment. J Clin Pharmacol. 2015;55(8):944–52. doi:10.1002/jcph.504.

    CAS  Article  PubMed  Google Scholar 

  49. Ramanathan S, Jin F, Sharma S, Kearney BP. Clinical pharmacokinetic and pharmacodynamic profile of idelalisib. Clin Pharmacokinet. 2016;55(1):33–45. doi:10.1007/s40262-015-0304-0.

    CAS  Article  PubMed  Google Scholar 

  50. Venclexta [package insert] Genentech. San Franscisco, CA. 2017.

  51. Cang S, Iragavarapu C, Savooji J, et al. ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development. J Hematol Oncol. 2015;8:129. doi:10.1186/s13045-015-0224-3.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–8. doi:10.1038/nm.3048.

    CAS  Article  PubMed  Google Scholar 

  53. Roberts AW, Seymour JF, Brown JR, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012;30(5):488–96. doi:10.1200/JCO.2011.34.7898.

    CAS  Article  PubMed  Google Scholar 

  54. Kipps TJ, Eradat H, Grosicki S, et al. A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia. Leuk Lymphoma. 2015;56(10):2826–33. doi:10.3109/10428194.2015.1030638.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–22. doi:10.1056/NEJMoa1513257.

    CAS  Article  PubMed  Google Scholar 

  56. Ma S, Brander DM, Seymour JF, et al. Deep and durable responses following venetoclax (ABT-199/GDC-0199) combined with rituximab in patients with relapsed/refractory chronic lymphocytic leukemia: results from a phase 1b study. Blood. 2015;126(23):830.

    Google Scholar 

  57. Eichhorst BF, Schetelig J, Coutre S, et al. Venetoclax (ABT-199/GDC-0199) monotherapy induces deep remissions, including complete remission and undetectable MRD, in ultra-high risk relapsed/refractory chronic lymphocytic leukemia with 17p deletion: results of the pivotal international phase 2 study. Blood. 2015;126(23):LBA6.

    Google Scholar 

  58. Davids MS, Pagel JM, Kahl BS, et al. Bcl-2 inhibitor ABT-199 (GDC-0199) monotherapy shows anti-tumor activity including complete remissions in high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Blood. 2013;122(21):872.

    Google Scholar 

  59. Freise KJ, Dunbar M, Jones AK, et al. Venetoclax does not prolong the QT interval in patients with hematological malignancies: an exposure-response analysis. Cancer Chemother Pharmacol. 2016;78(4):847–53. doi:10.1007/s00280-016-3144-1.

    CAS  Article  PubMed  Google Scholar 

  60. Jones AK, Freise KJ, Agarwal SK, et al. Clinical predictors of venetoclax pharmacokinetics in chronic lymphocytic leukemia and non-Hodgkin’s lymphoma patients: a pooled population pharmacokinetic analysis. AAPS J. 2016;18(5):1192–202. doi:10.1208/s12248-016-9927-9.

    CAS  Article  PubMed  Google Scholar 

  61. Agarwal SK, Hu B, Chien D, et al. Evaluation of rifampin’s transporter inhibitory and CYP3A inductive effects on the pharmacokinetics of venetoclax, a Bcl-2 inhibitor: results of a single- and multiple-dose study. J Clin Pharmacol. 2016;56(11):1335–43. doi:10.1002/jcph.730.

    CAS  Article  PubMed  Google Scholar 

  62. Salem AH, Agarwal SK, Dunbar M, et al. Pharmacokinetics of venetoclax, a novel BCL-2 inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or non-Hodgkin’s lymphoma. J Clin Pharmacol. 2016;. doi:10.1002/jcph.821.

    Google Scholar 

  63. Salem AH, Agarwal S, Dunbar M, et al. Effect of low and high fat meals on the pharmacokinetics of venetoclax, a selective first-in-class Bcl-2 inhibitor. J Clin Pharmacol. 2016;56(11):1355–61. doi:10.1002/jcph.741.

    CAS  Article  PubMed  Google Scholar 

  64. Freise KJ, Jones AK, Eckert D, et al. Impact of venetoclax exposure on clinical efficacy and safety in patients with relapsed or refractory chronic lymphocytic leukemia. Clin Pharmacokinet. 2016;. doi:10.1007/s40262-016-0453-9.

    Google Scholar 

  65. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768–78. doi:10.1016/S1470-2045(16)30019-5.

    CAS  Article  PubMed  Google Scholar 

  66. Jones J, Mato AR, Coutre S, et al. Preliminary results of a phase 2, open-label study of venetoclax (ABT-199/GDC-0199) monotherapy in patients with chronic lymphocytic leukemia relapsed after or refractory to ibrutinib or idelalisib therapy. Blood. 2015;126(23):715.

    Google Scholar 

  67. US Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm. Accessed 3 March 2017.

Download references

Author information

Affiliations

  1. Department of Pharmacy, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, 44195, USA

    Madeline Waldron

  2. Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA

    Allison Winter & Brian T. Hill

Authors
  1. Madeline Waldron
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Allison Winter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brian T. Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Madeline Waldron.

Ethics declarations

Conflict of interest

Dr. Brian Hill serves on the advisory board for Pharmacyclics and Gilead. He has received research funding from Abbvie and Gilead. Dr. Allison Winter and Dr. Madeline Waldron have no conflicts of interest to report that are directly relevant to the content of this article.

Funding

No funding was received in the preparation of this manuscript.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Waldron, M., Winter, A. & Hill, B.T. Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Chronic Lymphocytic Leukemia: Ibrutinib, Idelalisib, and Venetoclax. Clin Pharmacokinet 56, 1255–1266 (2017). https://doi.org/10.1007/s40262-017-0529-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-017-0529-1

Keywords

  • Chronic Lymphocytic Leukemia
  • Grapefruit Juice
  • CYP3A4 Inhibitor
  • Chronic Lymphocytic Leukemia Cell
  • Absolute Lymphocyte Count