nach oben

Clinical Pharmacokinetics

Erschienen in:

25.03.2017 | Review Article

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

verfasst von: Madeline Waldron, Allison Winter, Brian T. Hill

Erschienen in: Clinical Pharmacokinetics | Ausgabe 11/2017

Einloggen, um Zugang zu erhalten

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.

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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

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

10.

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

11.

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

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.CrossRefPubMed

13.

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

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRef

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.

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.

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.

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.

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.

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.

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.CrossRefPubMed

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.

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.CrossRefPubMed

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.

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.

Titel: Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Chronic Lymphocytic Leukemia: Ibrutinib, Idelalisib, and Venetoclax
verfasst von: Madeline Waldron
Allison Winter
Brian T. Hill
Publikationsdatum: 25.03.2017
Verlag: Springer International Publishing
Erschienen in: Clinical Pharmacokinetics / Ausgabe 11/2017
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-017-0529-1

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 11/2017

A Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Vedolizumab

Time-to-Seizure Modeling of Lacosamide Used in Monotherapy in Patients with Newly Diagnosed Epilepsy

Levetiracetam Clinical Pharmacokinetic Monitoring in Pediatric Patients with Epilepsy

Population Pharmacokinetic Modeling of JNJ-53718678, a Novel Fusion Inhibitor for the Treatment of Respiratory Syncytial Virus: Results from a Phase I, Double-Blind, Randomized, Placebo-Controlled First-in-Human Study in Healthy Adult Subjects

Development of a Pediatric Physiologically-Based Pharmacokinetic Model of Clindamycin Using Opportunistic Pharmacokinetic Data

Population Pharmacokinetic Analysis of Ixazomib, an Oral Proteasome Inhibitor, Including Data from the Phase III TOURMALINE-MM1 Study to Inform Labelling