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Clinical Pharmacokinetics and Pharmacodynamics of Bosutinib

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Abstract

Chronic myeloid leukemia (CML) is a clonal myeloproliferative stem cell disorder. Bosutinib is an oral, once-daily SRC/ABL tyrosine kinase inhibitor with very potent inhibitory activity. Bosutinib is effective against all phases of intolerant or resistant Philadelphia chromosome–positive CML that do not harbor the T315I or V299LABL kinase domain mutations. Peak plasma concentrations of bosutinib occur at 4–6 h following oral administration, and dose-proportional increases in exposure are observed at doses ranging from 200 to 800 mg. Absorption of bosutinib increases with food. Bosutinib is distributed extensively into the tissues. It is highly plasma protein bound (94 %) and is primarily metabolized in the liver by cytochrome P450 3A4. Bosutinib is well tolerated overall and has a unique but manageable toxicity profile. This article provides a review of the available clinical pharmacokinetic, pharmacodynamic, and drug–drug interaction data on bosutinib in healthy subjects, patients with CML, and special populations.

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References

  1. Konig H, Holyoake T, Bhatia R. Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual SRC/ABL kinase inhibitor SKI-606. Blood. 2008;111(4):2329–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sawyers C. Chronic myeloid leukemia. N Engl J Med. 1999;340(17):1330–40.

    Article  CAS  PubMed  Google Scholar 

  3. Thielen N, Ossenkoppele GJ, Schuurhuis GJ, Janssen J. New insights into the pathogenesis of chronic myeloid leukaemia: towards a path to cure. Neth J Med. 2011;69(10):430–40.

    CAS  PubMed  Google Scholar 

  4. Von Bubnoff N, Duyster J. Chronic myelogenous leukemia—treatment and monitoring. Dtsch Arztebl Int. 2010;107(7):114–21.

    Google Scholar 

  5. Florean C, Schnekenburger M, Grandjenette C, Dicato M, Diederich M. Epigenomics of leukemia: from mechanisms to therapeutic applications. Epigenomics. 2011;3(5):581–609.

    Article  CAS  PubMed  Google Scholar 

  6. Gugliotta G, Castagnetti F, Palandri F, Baccarani M, Rosti G. Imatinib in chronic myeloid leukemia elderly patients. Aging. 2011;3(12):1125–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Perrotti D, Jamieson C, Goldman J, Skorski T. Chronic myeloid leukemia: mechanisms of blastic transformation. J Clin Invest. 2010;120(7):2254–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Haznedaroglu IC. Drug therapy in the progressed CML patient with multi-TKI failure. Mediterr J Hematol Infect Dis. 2015;7(1):e2015014.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science. 2000;289:1938–42.

    Article  CAS  PubMed  Google Scholar 

  10. Deininger MW, O’Brien SG, Ford JM, Druker BJ. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol. 2003;21(8):1637–47.

    Article  CAS  PubMed  Google Scholar 

  11. Weisberg E, Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat Rev Cancer. 2007;7(5):345–56.

    Article  CAS  PubMed  Google Scholar 

  12. Ramirez P, DiPersio JF. Therapy options in imatinib failures. Oncologist. 2008;13(4):424–34.

    Article  CAS  PubMed  Google Scholar 

  13. Marega M, Piazza RG, Pirola A, Redaelli S, Mogavero A, Lacobucci I, et al. BCR and BCR-ABL regulation during myeloid differentiation in healthy donors and in chronic phase/blast crisis CML patients. Leukemia. 2010;24(8):1445–9.

    Article  CAS  PubMed  Google Scholar 

  14. Hochhaus A, Baccarani M, Deininger M, Apperley JF, Lipton JH, Goldberg SL, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008;22(6):1200–6.

    Article  CAS  PubMed  Google Scholar 

  15. Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, et al. Dasatinib in imatinib-resistant Philadelphia chromosome–positive leukemias. N Engl J Med. 2006;354(24):2531–41.

    Article  CAS  PubMed  Google Scholar 

  16. Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109(6):2303–9.

    Article  CAS  PubMed  Google Scholar 

  17. Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome–positive ALL. N Engl J Med. 2006;354(24):2542–51.

    Article  PubMed  Google Scholar 

  18. Kantarjian H, Pasquini R, Levy V, Jootar S, Holowiecki J, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R). Cancer. 2009;115(18):4136–47.

    Article  CAS  PubMed  Google Scholar 

  19. Weisberg E, Manley P, Breitenstein W, Brigger J, Cowan Jocab SW, Ray A, et al. Characterization of AMN107, a selective inhibitor of native and mutant BCR-ABL. Cancer Cell. 2005;7(2):129–41.

    Article  CAS  PubMed  Google Scholar 

  20. Ciarcia R, Damiano S, Puzo MV, Montagnaro S, Pagnini F, Pacilio C, et al. Comparison of dasatinib, nilotinib and imatinib in the treatment of chronic myeloid leukemia. J Cell Physiol. 2016;231(3):680–7.

    Article  CAS  PubMed  Google Scholar 

  21. Shah N, Tran C, Lee F, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399–401.

    Article  CAS  PubMed  Google Scholar 

  22. Tokarski J, Newitt J, Chang C, Cheng JD, Witterkind M, Kieffer SE, et al. The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res. 2006;66:5790–7.

    Article  CAS  PubMed  Google Scholar 

  23. Khoury HJ, Guilhot F, Hughes TP, Kim DW, Cortes JE. Dasatinib treatment for Philadelphia chromosome–positive leukemias: practical considerations. Cancer. 2009;115(7):1381–94.

    Article  CAS  PubMed  Google Scholar 

  24. Monge KS, Galvez-Ruiz A, Alvarez-Carron A, Quijada C, Matteu A. Optic neuropathy secondary to dasatinib in the treatment of a chronic myeloid leukemia case. Saudi J Ophthalmol. 2015;29:227–31.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kostos L, Burbury K, Srivastava G, Prince HM. Gastrointestinal bleeding in a chronic myeloid leukaemia patient precipitated by dasatinib-induced platelet dysfunction: case report. Platelets. 2015;1:1–3.

    Google Scholar 

  26. Cortes JE, Kim DW, Kantarjian HM, Brummendorf TH, Dyagil I, Griskericius L, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012;30(28):3486–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Golas M, Arndt K, Etienne C, Lucas J, Nardin D, Gibbons J, et al. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of SRC and ABL kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res. 2003;63:375–81.

    CAS  PubMed  Google Scholar 

  28. Puttini M, Coluccia AM, Boschelli F, Cleris L, Marches E, Donella-Deana A, et al. In vitro and in vivo activity of SKI-606, a novel SRC-ABL inhibitor, against imatinib-resistant BCR-ABL+ neoplastic cells. Cancer Res. 2006;66:11314–22.

    Article  CAS  PubMed  Google Scholar 

  29. Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009;27:469–71.

    Article  CAS  PubMed  Google Scholar 

  30. Cortes JE, Kantarjian HM, Brummendorf TH, Kim DW, Turkina AG, Shen ZX, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome–positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011;118:4567–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gambacorti-Passerini C, Kantarjian H, Bruemmendorf T. Bosutinib (SKI-606) demonstrates clinical activity and is well tolerated among patients with AP and BP CML and Ph+ ALL. Blood. 2007;110:473.

    Article  Google Scholar 

  32. Bruemmendorf TH, Cervantes F, Kim D, Chandy TM, Fischer T, Hochhaus A, et al. Bosutinib is safe and active in patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML) with resistance or intolerance to imatinib and other tyrosine kinase inhibitors [abstract no. 7001]. J Clin Oncol. 2008;26(15 Suppl.):372s.

    Google Scholar 

  33. García-Gutierrez V, Maestro B, Martinez-Trillo A, Lopez Lorenzo JL, Martin Marteos ML, Alvarez A, et al. Bosutinib appears to be safe, with low cross intolerance, in patients treated in 4th line: results of the Spanish Compassionate Use Program. Blood. 2014;124:5523.

    Google Scholar 

  34. García-Gutierrez V, Maestro B, Martinez-Trillo A, Bautista G, Martin Mateos ML, Alvarez Larran A, et al. Bosutinib shows low cross intolerance, in chronic myeloid leukemia patients treated in fourth line: results of the Spanish Compassionate Use Program. Am J Hematol. 2015;90(5):429–33.

    Article  PubMed  Google Scholar 

  35. Pfizer Ltd. Summary of product characteristics: Bosulif 100 mg film-coated tablets. London: European Medicines Agency; 2014. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002373/human_med_001613.jsp&mid=WC0b01ac058001d124. Accessed 19 Mar 2016.

  36. Abbas R, Hug BA, Leister C, Gaaloul ME, Chalon S, Sonnichsen D. A phase 1 ascending single-dose study of the safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects. Cancer Chemother Pharmacol. 2012;69:221–7.

    Article  CAS  PubMed  Google Scholar 

  37. Abbas R, Hug B, Leister C, Burns J, Sonnichsen D. Effect of ketoconazole on the pharmacokinetics (PK) of bosutinib (SKI-606) in healthy subjects. J Clin Pharmacol. 2011;51(12):1721–7.

    Article  CAS  PubMed  Google Scholar 

  38. Abbas R, Boni J, Sonnichsen D. Effect of rifampin on the pharmacokinetics of bosutinib, a dual SRC/ABL tyrosine kinase inhibitor, when administered concomitantly to healthy subjects. Drug Metabol Personal Ther. 2015;30(1):57–63.

    Article  CAS  PubMed  Google Scholar 

  39. Hsyu PH, Mould DR, Abbas R, Amantea M. Population pharmacokinetic and pharmacodynamic analysis of bosutinib. Drug Metab Pharmacokinet. 2014;29(6):1–8.

    Article  Google Scholar 

  40. US Food and Drug Administration Center for Drug Evaluation and Research [CDER]. Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system: guidance for industry. Rockville: CDER; 2000. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm128219. Accessed 11 May 2011.

  41. Hsyu PH, Matschke K, Soriano-Pignataro D. Absolute bioavailability of bosutinib in healthy subjects from an open-label, randomized, 2-period crossover study [abstract]. In: 2016 Annual Meeting, American Society for Clinical Pharmacology and Therapeutics; San Diego; 8–12 Mar 2016.

  42. Abbas R, Leister C, Sonnichsen D. A Clinical study to examine the potential effect of lansoprazole on the pharmacokinetics of bosutinib when administered concomitantly to healthy subjects. Clin Drug Investig. 2013;33:589–95.

    Article  CAS  PubMed  Google Scholar 

  43. Abbas-Borhan R, Chaudhary I, Hug BA, Leister C, Burns J, Vashishtha S, et al. Mass balance, metabolic disposition, metabolite characterization, and pharmacokinetics of oral 14C-labeled bosutinib in healthy subjects [poster no. P350]. In: 9th Triennial Meeting, International Society for the Study of Xenobiotics; Istanbul; 4–8 Sept 2010.

  44. Daud A, Krishnamurthi S, Saleh M, Gitlitz BJ, Borad MJ, Gold PJ, et al. Phase 1 study of bosutinib, a SRC/ABL tyrosine kinase inhibitor, administered to patients with advanced solid tumors. Clin Cancer Res. 2012;18(4):1092–100.

    Article  CAS  PubMed  Google Scholar 

  45. Yasuda SU, Zhang L, Huang SM. The role of ethnicity in variability in response to drugs: focus on clinical pharmacology studies. Clin Pharmacol Ther. 2008;84:417–23.

    Article  CAS  PubMed  Google Scholar 

  46. Nakaseko C, Takahashi N, Ishizawa K, Kobayashi Y, Ohashi K, Nakagawa Y, et al. A phase 1/2 study of bosutinib in Japanese adults with Philadelphia chromosome–positive chronic myeloid leukemia. Int J Hematol. 2015;101(2):154–64.

    Article  CAS  PubMed  Google Scholar 

  47. Hsyu PH, Gogat K, Duvillie L, Kelly V, Besson N. Pharmacokinetics and tolerability of bosutinib in Asian versus non-Asian patients with Philadelphia chromosome–positive leukemia. Blood. 2012;120(21):4440.

    Google Scholar 

  48. Abbas R, Chalon S, Leister C, EI Gaaloul M, Sonnichsen D. Evaluation of the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects. Cancer Chemother Pharmacol. 2013;71:123–32.

    Article  CAS  PubMed  Google Scholar 

  49. PRODUCT MONOGRAPH - BOSULIF™, Kirkland, Quebec: Pfizer Canada Inc; 2014. http://www.pfizer.ca/sites/g/files/g10017036/f/201410/BOSULIF.pdf. Accessed 31 Mar 2016.

  50. Boschelli DH, Ye F, Wang YD, Dutia M, Johnson SL, Wu B, et al. Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of SRC kinase activity. J Med Chem. 2001;44:3965–77.

    Article  CAS  PubMed  Google Scholar 

  51. Boschelli DH. Exploitation of the 3-quinolinecarbonitrile template for SRC tyrosine kinase inhibitors. Curr Top Med Chem. 2008;8(10):922–34.

    Article  CAS  PubMed  Google Scholar 

  52. Boschelli F, Arndt K, Gambacorti-Passerini C. Bosutinib: a review of preclinical studies in chronic myelogenousleukaemia. Eur J Cancer. 2010;46:1781–9.

    Article  CAS  PubMed  Google Scholar 

  53. Witte O. The role of BCR-ABL in chronic myeloid leukemia and stem cell biology. Semin Hematol. 2001;38(3 Suppl 8):3–8.

    Article  CAS  PubMed  Google Scholar 

  54. Remsing LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, et al. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009;23:477–85.

    Article  Google Scholar 

  55. Bantscheff M, Eberhard D, Abraham Y, Hantschel O, Bennett KL, Stranzl T, et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol. 2007;25:1035–44.

    Article  CAS  PubMed  Google Scholar 

  56. Konig H, Holyoake TL, Bhatia R. Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual SRC/ABL kinase inhibitor SKI-606. Blood. 2008;111:2329–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Thomas SM, Brugge JS. Cellular functions regulated by SRC family kinases. Annu Rev Cell Dev Biol. 1997;13:513–609.

    Article  CAS  PubMed  Google Scholar 

  58. Boschelli DH, Boschelli F, Wu B, Ye F, Wang Y, Golas JM, et al. SKI-606 and beyond. Hematol Rep. 2005;1(8):28–31.

    CAS  Google Scholar 

  59. Hsyu PH, Mould DR, Upton RN, Amantea M. Pharmacokinetic–pharmacodynamic relationship of bosutinib in patients with chronic phase chronic myeloid leukemia. Cancer Chemother Pharmacol. 2013;71:209–18.

    Article  CAS  PubMed  Google Scholar 

  60. Abbas R, Hug BA, Leister C, Sonnichsen D. A randomized, crossover, placebo- and moxifloxacin-controlled study to evaluate the effects of bosutinib (SKI-606), a dual SRC/ABL tyrosine kinase inhibitor, on cardiac repolarization in healthy adult subjects. Int J Cancer. 2012;131:E304–11.

    Article  CAS  PubMed  Google Scholar 

  61. Abbas R, Leister C, El Gaaloul M, Chalon S, Sonnichsen D. Ascending single-dose study of the safety profile, tolerability, and pharmacokinetics of bosutinib coadministered with ketoconazole to healthy adult subjects. Clin Ther. 2012;34(9):2011–9.

    Article  CAS  PubMed  Google Scholar 

  62. Chintakuntlawar AV, Finnes HD, Tefferi A, Pardanani A. Drug drug interaction between bosutinib and warfarin. Leuk Lymphoma. 2014;55(9):2213–4.

    Article  PubMed  Google Scholar 

  63. Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C, Watkins PB. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest. 1992;90:1871–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hsyu PH, Matschke K, Soriano-Pignataro D. An open-label, randomized, 2-period crossover study to evaluate the effect of a single oral dose of aprepitant, a moderate CYP3A inhibitor on bosutinib administered orally to healthy subjects [poster no. W5231]. In: 2015 Annual Meeting, American Association of Pharmaceutical Scientists; Orlando; 25–29 Oct 2015.

  65. Hsyu PH, Matschke K, Soriano-Pignataro D. An open-label, randomized, 2-period crossover study to evaluate the effect of a single oral dose of bosutinib on the pharmacokinetics of dabigatran etexilate mesylate administered orally to healthy subjects [poster no. W5230]. In: 2015 Annual Meeting, American Association of Pharmaceutical Scientists; Orlando; 25–29 Oct 2015.

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  1. Pfizer Inc, 500 Arcola Road, Collegeville, PA, 19426, USA

    Richat Abbas

  2. Pfizer Inc, San Diego, CA, USA

    Poe-Hirr Hsyu

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Correspondence to Richat Abbas.

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The authors, Richat Abbas and Poe-Hirr Hsyu, are employees of Pfizer, Inc., and own stocks in Pfizer, Inc.

This article is a review of previous published manuscripts by Wyeth Research and Pfizer, Inc. and clinical studies sponsored by Pfizer, Inc. Wyeth Research was acquired by Pfizer, Inc. in October 2009. Editorial/medical writing support was provided by Anand Kolla, PhD, of MakroCare, Inc., sponsored by Pfizer, Inc.

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Abbas, R., Hsyu, PH. Clinical Pharmacokinetics and Pharmacodynamics of Bosutinib. Clin Pharmacokinet 55, 1191–1204 (2016). https://doi.org/10.1007/s40262-016-0391-6

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