Nilotinib

Nilotinib

Systematic (IUPAC) name
4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide
Clinical data
Trade names	Tasigna
AHFS/Drugs.com	monograph
MedlinePlus	a608002
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	D (US)
Legal status	POM (UK) ℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	30%
Protein binding	98%
Metabolism	hepatic
Half-life	17 h
Excretion	biliary
Identifiers
CAS number	641571-10-0(base) N
ATC code	L01XE08
PubChem	CID 644241
DrugBank	DB04868
ChemSpider	559260 Y
UNII	F41401512X Y
KEGG	D08953 Y
ChEBI	CHEBI:52172 Y
ChEMBL	CHEMBL255863 Y
Chemical data
Formula	C28H22F3N7O
Mol. mass	529.5245 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C28H22F3N7O/c1-17-5-6-19(10-25(17)37-27-33-9-7-24(36-27)20-4-3-8-32-14-20)26(39)35-22-11-21(28(29,30)31)12-23(13-22)38-15-18(2)34-16-38/h3-16H,1-2H3,(H,35,39)(H,33,36,37) Y Key:HHZIURLSWUIHRB-UHFFFAOYSA-N Y
N (what is this?)  (verify)

Nilotinib (AMN107, trade name Tasigna), in the form of the hydrochloride monohydrate salt, is a tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia.

Uses

Crystal structure of Abl kinase domain (blue) in complex with nilotinib (red)

Nilotinib was approved as Tasigna in the USA and the EU for drug-resistant chronic myelogenous leukemia (CML). In June 2006, a Phase I clinical trial found nilotinib has a relatively favorable safety profile and shows activity in cases of CML resistant to treatment with imatinib (trade name: Gleevec [USA]/ Glivec [Europe/Australia/Latin America]), another tyrosine kinase inhibitor currently used as a first-line treatment. In that study 92% of patients (already resistant or unresponsive to imatinib) achieved a normal white blood cell counts after five months of treatment. The drug carries a black box warning for possible heart complications.

Pharmacology

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. The clinical importance of nilotinib’s greater binding affinity is not established in patients with imatinib-susceptible disease. Nilotinib absorption greatly decreases with increasing dose above 400 mg. Absorption increases significantly in the presence of food. The clinical course of CML begins with an indolent chronic phase, but can quickly progress to the more aggressive accelerated, then blast phases if left untreated. Disease classification is based on the degree of cell abnormality in the blood and bone marrow. Nearly 85% of patients are diagnosed during the chronic stage, when treatment is most effective. Diagnosis is often made from a routine blood test wherein leukocytosis (up to 1000 × 109/L) is found. Disease staging is primarily based on percent of blasts in the blood and bone marrow. Staging criteria vary between guidelines. Most CML studies follow criteria established at M.D. Anderson Cancer Center. The World Health Organization (WHO) guidelines propose a lower threshold for the acute and blastic phases of CML. Other criteria such as clonal evolution and platelet abnormalities also contribute to disease staging. Patients in the blastic phase with symptoms of malaise, fever, and worsening splenomegaly are considered to be in blast crisis.

Recommended Dosing

FDA (USA): 400 mg orally twice daily, approximately 12 hours apart and should not be taken with food. The capsules should be swallowed whole with water. No food should be consumed for at least 2 hours before the dose is taken and no food should be consumed for at least one hour after. Dose adjustment may be required for hematologic and non-hematologic toxicities, and drug interactions.

Europe (EMEA): The recommended dose of nilotinib is 400 mg twice daily. Treatment should be continued as long as the patient continues to benefit. Nilotinib should be taken twice daily approximately 12 hours apart and must not be taken with food. The capsules should be swallowed whole with water. No food should be consumed for 2 hours before the dose is taken and no food should be consumed for at least one hour after the dose is taken. Nilotinib may be given in combination with haematopoietic growth factors such as erythropoietin or granulocyte colony-stimulating factor (G-CSF) if clinically indicated. Nilotinib may be given with hydroxyurea or anagrelide if clinically indicated.

Black Box Warning (USA)

Nilotinib prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. Nilotinib should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to nilotinib administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

Regulatory status

First Approved

US FDA: August 2007
Europe (EMEA): 19 November 2007

Orphan designation

On 22 May 2006, orphan designation (EU/3/06/375) was granted by the European Commission to Novartis Europharm Limited, United Kingdom, for nilotinib for the treatment of chronic myeloid leukemia CML).

Marketing Authorization

Europe (EMEA): EU/1/07/422/001-004

Approved Indication

FDA (USA): Nilotinib, second generation oral kinase inhibitor indicated for the treatment of chronic phase and accelerated phase Philadelphia-chromosome-positive Chronic Myelogenous Leukemia (CML) in adult patients.

Europe (EMEA): Nilotinib is authorised in the European Union for the treatment of Philadelphia-chromosome-positive Chronic Myelogenous Leukaemia (CML).

Guidelines

USA (NCCN):The National Comprehensive Cancer Network (NCCN) recommends nilotinib for CML (grade 2A) as follows: Follow-up therapy after primary treatment with imatinib in patients with the following indications: no hematologic remission or in hematologic relapse at 3 months, no cytogenetic response at 6 months, minor or no cytogenetic response or in cytogenetic relapse at 12 months, partial, minor, or no cytogenetic response or in cytogentic relapse at 18 months; post-transplant follow-up treatment in patients with the following indications: molecular relapse (polymerase chain reaction positive) following cytogenetic remission, cytogenetic relapse or those who are not in cytogenetic remission; for the treatment of CML in accelerated phase in patients with disease progression on imatinib therapy; alternative treatment for patients with the following indications: severe hepatotoxicity due to imatinib therapy, severe nonhematologic toxicity due to imatinib or dasatinib therapy. The NCCN also recommends nilotinib for the treatment of GIST (grade 2A) for progressive disease when patient is no longer receiving benefit from imatinib or sunitinib.

Europe (NICE): A National Institute for Health and Clinical Excellence (NICE) assessment for nilotinib is pending.

External Links

• Discovery and development of Bcr-Abl tyrosine kinase inhibitors
• New drug information/Abbriviated Scientific Narrative
• Highlights of Prescription information Nilotinib (August 2007) Novartis Pharmaceuticals Corporation (USA)
• Summary of Product Characteristics Nilotinib (November 2007) Novartis AG ((Europe)