Nilotinib: A second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia

David L. DeRemer, Celalettin Ustun, Kavita Natarajan

Research output: Contribution to journalArticlepeer-review

135 Scopus citations


Background: Nilotinib, a second-generation tyrosine kinase inhibitor (TKI) formerly known as AMN107, was approved by the US Food and Drug Administration (FDA) on October 29, 2007, for the treatment of adult patients with chronic-phase (CP) and acceleratedphase (AP) Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) resistant to or intolerant of prior treatment that included imatinib. Objective: The purpose of this review was to evaluate the pharmacology, pharmacokinetic properties, and pharmacodynamic properties of nilotinib; results of clinical trials in patients with CML, Ph+ acute lymphoblastic leukemia (ALL), and gastrointestinal stromal tumors (GISTs); and potential drug interactions. Methods: Literature was identified and reviewed using searches of MEDLINE (1966-April 1, 2008), the American Society of Hematology and American Society of Clinical Oncology abstracts databases (2002-2008 annual meetings/symposia), the European Hematology Association abstracts database (2006-2007 annual meetings), and the American Association for Cancer Research symposia (2000-2007). Search terms included, but were not limited to, nilotinib, AMN107, chronic myelogenous leukemia, acute lymphoblastic leukemia, bcr-abl, imatinib resistance, adverse events, pharmacology, and clinical trials. Results: Nilotinib is an orally bioavailable derivative of imatinib with improved specificity toward the breakpoint cluster region-Abelson murine leukemia (bcr-abl) viral protooncogene. In preclinical studies, nilotinib was found to have activity against 32 of 33 imatinib-resistant bcr-abl mutations, but not against the T3151 mutation. On pharmacokinetic analysis, Tmax was 3 hours. The calculated t1/2 following multiple daily dosing was ~17 hours. The main metabolic pathways identified were oxidation and hydroxylation. The parent compound is the circulating component found in serum; the metabolites were not found to contribute to pharmacologic activity. Nilotinib is a competitive inhibitor of cytochrome P450 (CYP) 3A4, CYP2C8, CYP2C9, and CYP2D6. In 2 Phase II, openlabel, single-arm clinical studies, nilotinib was found to be beneficial in patients with CML that was imatinib resistant or intolerant. Overall, 58% of patients with CML-CP achieved a major cytogenetic response; 42%, a complete cytogenetic response; and 77%, a complete hematologic response (CHR). At 18 months, the estimated overall survival rate was 91%. Of patients whose disease had progressed to AP, nilotinib was associated with major cytogenetic response in 32%; complete cytogenetic response in 19%; and CHR in 30%. At 12 months, an estimated 56% of patients lacked progression of disease, and the estimated overall survival rate was 82%. Concurrent use of CYP3A4 inhibitors should be avoided. The most common toxicities attributable to nilotinib include rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, and vomiting. Grade 3/4 toxicities (≥10%) have included thrombocytopenia, neutropenia, elevated lipase, hyperglycemia, and hypophosphatemia. Nilotinib has been associated with a prolonged QT interval, and sudden death has been reported. The FDA-approved regimen of nilotinib is 400 mg PO BID on an empty stomach. Conclusions: Nilotinib is an oral second-generation bcr-abl TKI indicated for the treatment of imatinib resistant or -intolerant Ph+ CML-CP and -AP in adults. Positive clinical activity and tolerability have been reported in clinical trials. Clinical data on offlabel indications and in patients with Ph+ ALL and GIST continue to emerge.

Original languageEnglish (US)
Pages (from-to)1956-1975
Number of pages20
JournalClinical Therapeutics
Issue number11
StatePublished - Nov 2008


  • AMN107
  • acute lymphoblastic leukemia
  • adverse events
  • chronic myelogenous leukemia
  • gastrointestinal stromal tumor
  • imatinib resistance
  • nilotinib

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)


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