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Cited by 175Chronic Myeloid Leukemia TreatmentsChronic Lymphocytic Leukemia ResearchGastrointestinal Tumor Research and Treatment

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

DeRemer, David L., Ustun, Celalettin, Natarajan, Kavita·2008·Clinical Therapeutics
DOI 10.1016/j.clinthera.2008.11.014
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Abstract

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 accelerated-phase (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, T(max) was 3 hours. The calculated t((1/2)) following multiple daily dosing was approximately 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, open-label, 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 (> or = 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 off-label indications and in patients with Ph+ ALL and GIST continue to emerge.

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  • Nilotinib has been shown to prevent degeneration in murine models of AD.

    “Nilotinib, a c-Abl tyrosine kinase inhibitor already approved for the treatment of chronic myeloid leukemia, has been shown to prevent degeneration in murine models of AD [146,147].”

    From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [146]

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Authors
DeRemer, D. L., Ustun, C., & Natarajan, K.
Affiliations
  • University of Georgia (US)
  • Augusta University (US)
ORCID
DeRemer, David L.
Venue
Clinical Therapeutics
Publisher
Elsevier BV
Published
2008-11
Volume
30
Issue
11
Pages
1956-1975
ISSN
0149-2918 (ISSN-L)
DOI
10.1016/j.clinthera.2008.11.014
OpenAlex
W2031077231
Cited by
172
References
86
Citations by year
2026: 5 · 2025: 11 · 2024: 11 · 2023: 9 · 2022: 9 · 2021: 8 · 2020: 20 · 2019: 10 · 2018: 4 · 2017: 4 · 2016: 11 · 2015: 7 · 2014: 9 · 2013: 13 · 2012: 2
FWCI
1.77
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Clinical Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal Tumor Research and Treatment
Keywords
nilotinib, tyrosine kinase inhibitors, chronic myeloid leukemia, Philadelphia chromosome-positive leukemia, imatinib resistance, BCR-ABL mutations, T315I mutation, pharmacokinetics, pharmacodynamics, drug interactions, cytochrome P450 inhibition, gastrointestinal stromal tumor, acute lymphoblastic leukemia, adverse events, oral bioavailability
MeSH terms
Animals, Clinical Trials as Topic, Humans, Models, Biological, Protein-Tyrosine Kinases, Pyrimidines, Molecular Structure, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Fusion Proteins, bcr-abl, Gastrointestinal Stromal Tumors, Precursor Cell Lymphoblastic Leukemia-Lymphoma

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