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Arzneistoffprofil: Nilotinib

Präklinik – Pharmakologie – Klinische Wirksamkeit – Toxizitäten

Medication profile: nilotinib

Preclinical data – pharmacology – clinical effectiveness – toxicities

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Zusammenfassung

Nilotinib (AMN107) ist ein neuer, hoch selektiver and potenter Aminopyrimidin-Inhibitor der BCR-ABL-Tyrosinkinase, welcher in vitro um den Faktor 30 potenter als Imatinib ist. Nilotinib ist gegen 32 der 33 Mutationen wirksam, die zu einer Imatinib-Resistenz führen, mit Ausnahme der T315I-Mutation. Zusätzliche Aktivität besteht gegenüber KIT (c-KIT) sowie dem „platelet-derived growth factor receptor“ (PDGFR). Als Ergebnis dieser Eigenschaft, Tyrosinkinasen zielgerichtet zu hemmen, wurde Nilotinib bei der chronischen myeloischen Leukämie (CML), bei der Philadelphia-Chromosom-positiven akuten lymphatischen Leukämie (Ph+ALL) und anderen hämatologischen Malignomen (wie bei der systemischen Mastozytose und der chronischen eosinophilen Leukämie CEL) geprüft. Die präklinischen und klinischen Daten von Nilotinib demonstrieren dabei eine hohe Wirksamkeit gegen Imatinib-resistente, klinisch problematische Tyrosinkinase-Mutationen. Aufgrund dieser verbesserten pharmakologischen Eigenschaften wurde ein umfassendes klinisches Entwicklungsprogramm durchgeführt, welches zur Zulassung von Nilotinib in der Schweiz, den USA und in der EU im Jahre 2007 führte. Klinische Studien mit Nilotinib weisen ferner auf eine Aktivität gegen gastrointestinale Stromatumoren (GIST) hin.

Abstract

Nilotinib (AMN107) is a novel highly selective and potent aminopyrimidine inhibitor of BCR-ABL tyrosine kinase that in vitro is 30 times more potent than imatinib. Nilotinib was designed to be a highly specific inhibitor of BCR-ABL with greater potency than imatinib. Nilotinib is active against 32/33 imatinib-resistant BCR-ABL mutations Additional activity was demonstrated against KIT (c-KIT) as well as against platelet-derived growth factor receptor. In animal models of leukemia, nilotinib has been shown to prevent and delay development of chronic myelogenous leukemia and improve survival. Nilotinib has demonstrated favorable efficacy and tolerability in phase I/II and phase II trials of patients with imatinib-resistant and imatinib-intolerant Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia. Nilotinib is well tolerated, as evidenced by its safety profile and high dose intensity.

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Literatur

  1. Davies SL, Bolos J, Serradell N, Bayes M (2007) Nilotinib. Drugs of the Future 32(1): 17–25

    Article  CAS  Google Scholar 

  2. Demetri GD, Bauer S, Dileo P et al. (2005) Activity of AMN107, a novel kinase inhibitor, in gastrointestinal stromal tumor (GIST): Preclinical rationale and early clinical results with imatinib-resistant GIST. 17th AACR-NCI-EORTC Int Conf Mol Targets Cancer Ther (Philadelphia). Abstract A265

  3. Deininger MWN, Goldman JM, Melo JV (2000) The molecular biology of chronic myeloid leukemia. Blood 96: 3343–3356

    PubMed  CAS  Google Scholar 

  4. Druker B, Guilhot F, O‘Brien SG et al. (2007) Five-year follow-up of patients receiving imatinib for chronic myeloid leukaemia. NEJM 356(17): 1780

    Article  CAS  Google Scholar 

  5. Giles F, le Coutre P, Bhalla K et al. (2006) A phase II study of nilotinib, a novel tyrosine kinase inhibitor administered to patients with imatinib resistant or intolerant chronic myelogenous leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast crisis (BC) who have also failed dasatinib therapy. ASH Annu Meet Abstracts Part 1 108(11): 615a Abstract 2170

    Google Scholar 

  6. Giles F, le Coutre P, Bhalla K et al. (2007) Nilotinib therapy after dasatinib failure in patients with imatinib-resistant or -intolerant chronic myeloloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast crisis (BC). ASH Meeting Atlanta. Blood 10(11): (Abstract 1029)

  7. Golemovic M, Beran M, Giles F et al. (2004) AMN107, a novel aminopyrimidine inhibitor of BCR-ABL, is significantly more potent than imatinib mesylate against Philadelphia chromosome positive acute lymphoblastic leukemia cells. Blood 104(11): Abstract 1983

    Google Scholar 

  8. Golemovic, M Verstovsek S, Giles F et al. (2005) AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. Clin Cancer Res 11: 4941–4947

    Article  PubMed  CAS  Google Scholar 

  9. Griffin JD, Weisberg EL (2005) Simultaneous administration of AMN107 and imatinib in the treatment of imatinib-sensitive and imatinib-resistant chronic myeloid leukemia. Blood 47th Annu Meet Am Soc Hematol Atlanta 106(11): Abstract 694

    Google Scholar 

  10. Jabbour E, Kantarjian H, Giles F et al. (2006) Treatment with nilotinib for patients with chronic myeloid leukemia (CML) who failed prior therapy with imatinib und dasatinib. ASH Annu Meet Abstracts Part 1 108(11): 616a Abstract 2171

    Google Scholar 

  11. Jabbour E, le Coutre P, Baccarini M et al. (2007) Nilotinib is associated with minimal cross intolerance to imatinib in patients with imatinib-intolerant chronic myelogenous leukemia (CML) in chronic phase (CP). 43rd ASCO Annu Meet Proc Chicago: 366 s Abstract 7039

    Google Scholar 

  12. Kagan M, Tran P, Fischer V et al. (2005) Safety, pharmakokinetics (PK), metabolism, and mass balance of [14C]-AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl tyrosine kinase, in healthy subjects. Blood 47th Annu Meet Am Soc Hematol (Dec 10–13, Atlanta) 106(11): Abstract 4887

  13. Kantarjian HM, Giles F, Wunderle L et al. (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354: 2542–2551

    Article  PubMed  Google Scholar 

  14. Kantarjian HM, Giles F, Gattermann N et al. (2007) Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 110(10): 3540–3546

    Article  PubMed  CAS  Google Scholar 

  15. Larson R, Ottmann O, Kantarjian H et al. (2007) A phase II study of nilotinib administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL). 43rd ASCO Annu Meet Proc Chicago: 367 s Abstract 7040

    Google Scholar 

  16. le Coutre P, Baskaynak G, Tamm I et al. (2004) Activity and induction of apoptosis of the specific tyrosine kinase inhibitor AMN 107 in bcr-abl+ cell lines and in imatinib resistant primary cells from CML patients. Blood 104(11): Abstract 762

    Article  Google Scholar 

  17. le Coutre P, Baskaynak G, Tamm I et al. (2005) Activity and induction of apoptosis of the tyrosine kinase inhibitor AMN107 in bcr-abl+ cell lines and in imatinib resistant primary cells from CML patients. Proc Am Assoc Cancer Res (AACR) 46: Abstract 5987

    Google Scholar 

  18. le Coutre P, Gattermann N, Hochhaus A et al. (2007) A phase II study of nilotinib administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in accelerated phase (AP). 43rd ASCO Annu Meet Proc [Chicago]: 363 s, Abstract 7026

  19. le Coutre P, Ottmann O, Giles F et al. (2008) Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated phase chronic myelogenous leukemia. Blood 111(4): 1834–1839

    Article  Google Scholar 

  20. Manley P, von Bubnoff N, Duyster J et al. (2005) AMN107: inhibitory profile against wild-type and mutant forms of the BCR-ABL tyrosine kinase. 96th Annu Meet of the Am Assoc Cancer Res AACR Anaheim 16–20 Abstract

  21. Martinelli G, Martelli AM, Grafone T et al. (2004) A new Abl kinase inhibitor (AMN107) has in vitro activity on CML Ph+ blast cells resistant to imatinib. Blood 104(11): Abstract 4687

    Google Scholar 

  22. Martinelli G, Martelli AM, Grafone T et al. (2005) A new Abl kinase inhibitor (AMN107) has in vitro activity on chronic myeloid (CML) Ph+ cells resistant to imatinib. Blood 47th Annu Meet Am Soc Hematol (Atlanta) 106(11): Abstract 2004

    Google Scholar 

  23. Mestan J, Weisberg E, Cowan-Jocob S et al. (2004) AMN107: in vitro profile of a new inhibitor ot the tyrosine kinase activity of Bcr-Abl. Blood 104(11): Abstract 1978

    Google Scholar 

  24. Müller, MC, Branford S, Radich J et al. (2007) Response dynamics to nilotinib depend on the type of BCR-ABL mutations in patients with chronic myelogenous leukemia (CML) after imatinib failure. 43rd ASCO Annu Meet Proc Chicago: 363 s, Abstract 7024

    Google Scholar 

  25. O’Hare T, Walters DK, Stoffregen EP et al. (2005) In vitro activity of Bcr-Abl inhibitors ANM107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 65: 4500–4505

    Article  Google Scholar 

  26. Prenen H, Guetens G, de Boeck G et al. (2006) Cellular uptake of the tyrosine kinase inhibitors imatinib and AMN107 in gastrointestinal stromal tumor cell lines. Pharmacol 77: 11–16

    Article  CAS  Google Scholar 

  27. Tanaka C, Smith T, Kantarjian H et al. (2006) Clinical pharmakokinetics (PK) of AMN107, a novel inhibitor of Bcr-Abl, in healthy subjects and patients with imatinib resistant or intolerant chronic myelogenous leukemia (CML) or relapsed/refractory Ph+ acute lymphocytic leukemia (Ph+ ALL). J Clin Oncol 42nd ASCO Annu Meet Proc Atlanta 24(24): 18S Abstract 3095

    Google Scholar 

  28. Verstovsek S, Golemovic M, Kantarjian H et al. (2005) AMN107, a novel aminopyrimidine inhibitor of p190 BCR-ABL activation and of in vitro proliferation of Philadelphia-positive acute lymphoblastic leukemia cells. Cancer 104: 1230–1236

    Article  PubMed  CAS  Google Scholar 

  29. Verstovsek S, Giles FJ, Quintas-Cardama A et al. (2006) Activity of AMN107, a novel animopyrimidine tyrosin kinase inhibitor, against human FIP1L1-PDGFR-alpha-expressing cells. Leuk Res 30: 1499–1505

    Article  PubMed  CAS  Google Scholar 

  30. Von Bubnoff N, Manley PW, Mestan J et al. (2006) Bcr-Abl resistance screening predicts a limited spectrum of points mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107). Blood 108: 1328–1333

    Article  Google Scholar 

  31. Weisberg E, Manley PW, Breitenstein W et al. (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7: 129–141

    Article  PubMed  CAS  Google Scholar 

  32. Weisberg E, Manley P, Mestan J et al. (2006) AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer 94: 1765–1769

    Article  PubMed  CAS  Google Scholar 

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Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehung hin: Referententätigkeit und Reisekostenausgleich durch Novartis (Hersteller von Nilotinib).

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Authors and Affiliations

  1. Medizinische Klinik m.S. Hämatologie und Onkologie, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Deutschland

    P. le Coutre & C. Petereit

  2. Glashütten (früher: Med. Hochschule Hannover, Zentrum für Pharmakologie), Hannover, Deutschland

    H.-D. Peters

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  1. P. le Coutre
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  2. C. Petereit
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  3. H.-D. Peters
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Correspondence to P. le Coutre.

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le Coutre, P., Petereit, C. & Peters, HD. Arzneistoffprofil: Nilotinib. Onkologe 14, 940–950 (2008). https://doi.org/10.1007/s00761-008-1422-1

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  • DOI: https://doi.org/10.1007/s00761-008-1422-1

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