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

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 acceleratedphase (AP) Philadelphia chromosome-p...

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Bibliographic Details
Published in:Clinical therapeutics 2008-11, Vol.30 (11), p.1956-1975
Main Authors: DeRemer, David L., PharmD, BCOP, Ustun, Celalettin, MD, Natarajan, Kavita, MD
Format: Article
Language:English
Subjects:
acute lymphoblastic leukemia
adverse events
AMN107
Animals
Antineoplastic agents
Biological and medical sciences
Biology
Cancer
Chemotherapy
Chromosomes
chronic myelogenous leukemia
Clinical significance
Clinical Trials as Topic
Drug dosages
Fusion Proteins, bcr-abl
Gastroenterology. Liver. Pancreas. Abdomen
gastrointestinal stromal tumor
Gastrointestinal Stromal Tumors - drug therapy
Hematologic and hematopoietic diseases
Humans
imatinib resistance
Interferon
Internal Medicine
Kinases
Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Medical Education
Medical prognosis
Medical sciences
Models, Biological
Molecular Structure
Mutation
nilotinib
Pharmacokinetics
Pharmacology. Drug treatments
Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
Protein-Tyrosine Kinases - antagonists & inhibitors
Pyrimidines - adverse effects
Pyrimidines - chemistry
Pyrimidines - therapeutic use
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Tumors
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Summary: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 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 t½ 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
ISSN:0149-2918
1879-114X
DOI:10.1016/j.clinthera.2008.11.014