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01.09.2008 | Update Onkologie

Arzneistoffprofil: Nilotinib

Präklinik – Pharmakologie – Klinische Wirksamkeit – Toxizitäten

verfasst von: PD. Dr. P. le Coutre, C. Petereit, H.-D. Peters

Erschienen in: Die Onkologie | Ausgabe 9/2008

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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.
Literatur
1.
Zurück zum Zitat Davies SL, Bolos J, Serradell N, Bayes M (2007) Nilotinib. Drugs of the Future 32(1): 17–25CrossRef Davies SL, Bolos J, Serradell N, Bayes M (2007) Nilotinib. Drugs of the Future 32(1): 17–25CrossRef
2.
Zurück zum Zitat 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 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.
Zurück zum Zitat Deininger MWN, Goldman JM, Melo JV (2000) The molecular biology of chronic myeloid leukemia. Blood 96: 3343–3356PubMed Deininger MWN, Goldman JM, Melo JV (2000) The molecular biology of chronic myeloid leukemia. Blood 96: 3343–3356PubMed
4.
Zurück zum Zitat 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): 1780CrossRef 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): 1780CrossRef
5.
Zurück zum Zitat 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 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
6.
Zurück zum Zitat 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) 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.
Zurück zum Zitat 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 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
8.
Zurück zum Zitat 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: 4941–4947PubMedCrossRef 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: 4941–4947PubMedCrossRef
9.
Zurück zum Zitat 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 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
10.
Zurück zum Zitat 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 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
11.
Zurück zum Zitat 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 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
12.
Zurück zum Zitat 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 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.
Zurück zum Zitat Kantarjian HM, Giles F, Wunderle L et al. (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354: 2542–2551PubMedCrossRef Kantarjian HM, Giles F, Wunderle L et al. (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354: 2542–2551PubMedCrossRef
14.
Zurück zum Zitat 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): 3540–3546PubMedCrossRef 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): 3540–3546PubMedCrossRef
15.
Zurück zum Zitat 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 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
16.
Zurück zum Zitat 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 762CrossRef 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 762CrossRef
17.
Zurück zum Zitat 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 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
18.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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): 1834–1839CrossRef 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): 1834–1839CrossRef
20.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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
22.
Zurück zum Zitat 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 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
23.
Zurück zum Zitat 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 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
24.
Zurück zum Zitat 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 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
25.
Zurück zum Zitat 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: 4500–4505CrossRef 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: 4500–4505CrossRef
26.
Zurück zum Zitat 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: 11–16CrossRef 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: 11–16CrossRef
27.
Zurück zum Zitat 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 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
28.
Zurück zum Zitat 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: 1230–1236PubMedCrossRef 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: 1230–1236PubMedCrossRef
29.
Zurück zum Zitat 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: 1499–1505PubMedCrossRef 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: 1499–1505PubMedCrossRef
30.
Zurück zum Zitat 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: 1328–1333CrossRef 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: 1328–1333CrossRef
31.
Zurück zum Zitat Weisberg E, Manley PW, Breitenstein W et al. (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7: 129–141PubMedCrossRef Weisberg E, Manley PW, Breitenstein W et al. (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7: 129–141PubMedCrossRef
32.
Zurück zum Zitat Weisberg E, Manley P, Mestan J et al. (2006) AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer 94: 1765–1769PubMedCrossRef Weisberg E, Manley P, Mestan J et al. (2006) AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer 94: 1765–1769PubMedCrossRef
Metadaten
Titel
Arzneistoffprofil: Nilotinib
Präklinik – Pharmakologie – Klinische Wirksamkeit – Toxizitäten
verfasst von
PD. Dr. P. le Coutre
C. Petereit
H.-D. Peters
Publikationsdatum
01.09.2008
Verlag
Springer-Verlag
Erschienen in
Die Onkologie / Ausgabe 9/2008
Print ISSN: 2731-7226
Elektronische ISSN: 2731-7234
DOI
https://doi.org/10.1007/s00761-008-1422-1

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