Nilotinib (AMN107, trade name Tasigna) is a tyrosine kinase inhibitor of Bcr-Abl, rationally designed to bind and inhibit the c-Abl kinase active site with more affinity than the prototypic Bcr-Abl kinase inhibitor Imatinib. Nilotinib inhibits the kinases Bcr-Abl, KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11 and ZAK. Nilotinib possesses an in vitro Bcr-Abl binding potency 30 times greater than imatinib in imatinib-resistant cells, and 5-7 times greater than imatinib in imatinib-susceptible leukemic cells. Nilotinib also induces cell cycle arrest, accompanied by increased expression of p27 and downregulation of cyclin D1. Nilotinib (AMN107) is more potent than imatinib against CML cells by a factor of 20 to 50.
|Source||J Clin Pharmacol (2015). Figure 3. Nilotinib|
|Cell Lines||blood samples|
|Incubation Time||24, 48, and 72 h|
|Results||Following a single-dose of midazolam of 2 mg on Day 1, midazolam was rapidly absorbed and eliminated with a Cmax of 12.4 ng/mL and AUCinf of 37.0 ng.h/mL. Coadministration with repeated-doses of nilotinib increased the Cmax to 24.1 ng/mL and AUCinf to 88.8 ng.h/mL.|
|Source||J Clin Pharmacol (2015). Figure 2. Nilotinib|
|Results||The mean plasma concentration-time profiles of midazolam dosing alone and in combination with nilotinib are displayed in Figure 2a.|
|Cell lines||V560G-KIT and D816-KIT cell|
|Preparation method||Cell proliferation studies
Cells were incubated for 24 hours in complete medium containing up to 10 μmol/L of drug. Viable cells, based on cell size, were then counted using a CDA-500 cell counter (Sysmex Corp.). Duplicate samples at each drug concentration were averaged and cell proliferation then expressed as a percentage of cells in the vehicle control samples.
|Concentrations||0~10 μ M|
|Incubation time||24 h|
|Animal models||DBA2/J mice bearing a V560G-KIT and D816V-KIT tumor model|
|Formulation||10% N-methylpyrrolidinone, 90% polyethylene glycol 300|
|Dosages||100 mg/kg once daily|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 40 mg/mL|
Preclinical evaluation of nilotinib efficacy in an imatinib-resistant KIT-driven tumor model.
Cullinane C, et al. Mol Cancer Ther. 2010 May;9(5):1461-8. PMID: 20442311.
Extended kinase profile and properties of the protein kinase inhibitor nilotinib.
Manley PW, et al. Biochim Biophys Acta. 2010 Mar;1804(3):445-53. PMID: 19922818.
Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.
Kantarjian H, et al. N Engl J Med. 2006 Jun 15;354(24):2542-51. PMID: 16775235.
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