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Details

Stereochemistry ACHIRAL
Molecular Formula C28H22F3N7O.ClH.H2O
Molecular Weight 583.992
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of NILOTINIB HYDROCHLORIDE MONOHYDRATE

SMILES

O.Cl.CC1=CN(C=N1)C2=CC(=CC(NC(=O)C3=CC=C(C)C(NC4=NC=CC(=N4)C5=CC=CN=C5)=C3)=C2)C(F)(F)F

InChI

InChIKey=YCBPQSYLYYBPDW-UHFFFAOYSA-N
InChI=1S/C28H22F3N7O.ClH.H2O/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);1H;1H2

HIDE SMILES / InChI

Molecular Formula ClH
Molecular Weight 36.461
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Molecular Formula C28H22F3N7O
Molecular Weight 529.5158
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Molecular Formula H2O
Molecular Weight 18.0153
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/16721371 | https://www.ncbi.nlm.nih.gov/pubmed/19920925

Nilotinib (AMN107, trade name Tasigna) is a kinase inhibitor indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in adult patients resistant to or intolerant to prior therapy that included imatinib. Nilotinib is an inhibitor of the Bcr-Abl kinase. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of Abl protein. In vitro, nilotinib inhibited Bcr-Abl mediated proliferation of murine leukemic cell lines and human cell lines derived from Ph+ CML patients. Under the conditions of the assays, nilotinib was able to overcome imatinib resistance resulting from Bcr-Abl kinase mutations, in 32 out of 33 mutations tested. In vivo, nilotinib reduced the tumor size in a murine Bcr-Abl xenograft model. Nilotinib inhibited the autophosphorylation of the following kinases at IC50 values as indicated: Bcr-Abl (20-60 nM), PDGFR (69 nM) and c-Kit (210 nM). Nilotinib is currently being trialed in people with Parkinson's disease, as it appears to be able to halt progression of the disease and even improve their symptoms. The drug also has a number of adverse effects typical of anti-cancer drugs: a headache, fatigue, gastrointestinal problems such as nausea, vomiting, diarrhea and constipation, muscle and joint pain, rash and other skin conditions, flu-like symptoms, and reduced blood cell count. Less typical side effects are those of the cardiovascular system, such as hypertension (high blood pressure), various types of arrhythmia, and prolonged QT interval. Interaction of nilotinib with OATP1B1 and OATP1B3 may alter its hepatic disposition and can lead to transporter mediated drug-drug interactions. Nilotinib is an inhibitor of OATP-1B1 transporter but not for OATP-1B3. Main metabolic pathways identified in healthy subjects are oxidation and hydroxylation. Nilotinib is the main circulating component in the serum. None of the metabolites contributes significantly to the pharmacological activity of nilotinib.

Originator

Curator's Comment: # Novartis Pharmaceuticals Corporation

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
0.33 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
TASIGNA

Approved Use

Tasigna is a kinase inhibitor indicated for: The treatment of newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The treatment of chronic phase (CP) and accelerated phase (AP) Ph+ CML in adult patients resistant to or intolerant to prior therapy that included imatinib. (1.2) 1.1 Newly Diagnosed Ph+ CML-CP Tasigna (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of Tasigna is based on major molecular response and cytogenetic response rates [see Clinical Studies (14.1)

Launch Date

1.19361595E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
1550 ng/mL
400 mg 2 times / day steady-state, oral
dose: 400 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB serum
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
2300 ng/mL
400 mg 2 times / day steady-state, oral
dose: 400 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB serum
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: HIGH-FAT
3320 ng/mL
600 mg 2 times / day steady-state, oral
dose: 600 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB serum
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
6010 ng/mL
600 mg 2 times / day steady-state, oral
dose: 600 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB serum
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: HIGH-FAT
2190 ng/mL
800 mg 1 times / day steady-state, oral
dose: 800 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
2490 ng/mL
1200 mg 1 times / day steady-state, oral
dose: 1200 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
403 ng/mL
50 mg 1 times / day steady-state, oral
dose: 50 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
402.715 ng/mL
230 mg/m^2 single, oral
dose: 230 mg/m^2
route of administration: oral
experiment type: single
co-administered:
NILOTINIB plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status:
405.111 ng/mL
230 mg/m^2 single, oral
dose: 230 mg/m^2
route of administration: oral
experiment type: single
co-administered:
NILOTINIB plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status:
1360 ng/mL
300 mg 2 times / day steady-state, oral
dose: 300 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB plasma
Homo sapiens
population: UNHEALTHY
age: UNKNOWN
sex: FEMALE / MALE
food status: FASTED
1595 ng/mL
400 mg 2 times / day steady-state, oral
dose: 400 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB plasma
Homo sapiens
population: UNHEALTHY
age: UNKNOWN
sex: FEMALE / MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
12700 ng × h/mL
400 mg 2 times / day steady-state, oral
dose: 400 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB serum
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
18200 ng × h/mL
400 mg 2 times / day steady-state, oral
dose: 400 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB serum
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: HIGH-FAT
24500 ng × h/mL
600 mg 2 times / day steady-state, oral
dose: 600 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB serum
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
43100 ng × h/mL
600 mg 2 times / day steady-state, oral
dose: 600 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB serum
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: HIGH-FAT
26600 ng × h/mL
800 mg 1 times / day steady-state, oral
dose: 800 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
28000 ng × h/mL
1200 mg 1 times / day steady-state, oral
dose: 1200 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
4480 ng × h/mL
50 mg 1 times / day steady-state, oral
dose: 50 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
14383.076 ng*h/mL
230 mg/m^2 2 times / day steady, oral
dose: 230 mg/m^2
route of administration: oral
experiment type: steady
co-administered:
NILOTINIB plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status:
15129.182 ng*h/mL
230 mg/m^2 2 times / day steady, oral
dose: 230 mg/m^2
route of administration: oral
experiment type: steady
co-administered:
NILOTINIB plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status:
2795.78199999999 ng*h/mL
230 mg/m^2 single, oral
dose: 230 mg/m^2
route of administration: oral
experiment type: single
co-administered:
NILOTINIB plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status:
3393.296 ng*h/mL
230 mg/m^2 single, oral
dose: 230 mg/m^2
route of administration: oral
experiment type: single
co-administered:
NILOTINIB plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status:
4160.969 ng*h/mL
230 mg/m^2 single, oral
dose: 230 mg/m^2
route of administration: oral
experiment type: single
co-administered:
NILOTINIB plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status:
5707.368 ng*h/mL
230 mg/m^2 single, oral
dose: 230 mg/m^2
route of administration: oral
experiment type: single
co-administered:
NILOTINIB plasma
Homo sapiens
population: unhealthy
age: Children
sex:
food status:
11865 ng × h/mL
300 mg 2 times / day steady-state, oral
dose: 300 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB plasma
Homo sapiens
population: UNHEALTHY
age: UNKNOWN
sex: FEMALE / MALE
food status: FASTED
13656 ng × h/mL
400 mg 2 times / day steady-state, oral
dose: 400 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NILOTINIB plasma
Homo sapiens
population: UNHEALTHY
age: UNKNOWN
sex: FEMALE / MALE
food status: FASTED
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
1.6%
NILOTINIB plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
400 mg 2 times / day steady, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: steady
Dose: 400 mg, 2 times / day
Sources:
unhealthy, 56 years (range: 26-85 years)
n = 132
Health Status: unhealthy
Condition: Philadelphia chromosome positive chronic myelogenous leukemia - chronic phase ((CML-CP)
Age Group: 56 years (range: 26-85 years)
Sex: M+F
Population Size: 132
Sources:
Disc. AE: Thrombocytopenia, Neutropenia...
AEs leading to
discontinuation/dose reduction:
Thrombocytopenia (5 patients)
Neutropenia (1 patient)
Bilirubin increased (2 patients)
Hepatotoxicity (2 patients)
Skin rash (1 patient)
Sources:
600 mg 2 times / day steady, oral
MTD
Dose: 600 mg, 2 times / day
Route: oral
Route: steady
Dose: 600 mg, 2 times / day
Sources:
unhealthy, 56.2 ± 15.3 years
n = 18
Health Status: unhealthy
Condition: CML: blastic phase, accelerated phase, and chronic phase) | Ph-positive ALL
Age Group: 56.2 ± 15.3 years
Sex: M+F
Population Size: 18
Sources:
400 mg 2 times / day steady, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: steady
Dose: 400 mg, 2 times / day
Sources:
unhealthy, 59 years (range: 22-79 years)
n = 64
Health Status: unhealthy
Condition: Philadelphia chromosome positive chronic myelogenous leukemia - accelerated phase (CML-AP)
Age Group: 59 years (range: 22-79 years)
Sex: M+F
Population Size: 64
Sources:
Disc. AE: Rash, Pancreatitis...
AEs leading to
discontinuation/dose reduction:
Rash (1 patient)
Pancreatitis (1 patient)
Myocardial infarction (1 patient)
Thrombocytopenia (grade 3, 1 patient)
Neutropenia (grade 3, 1 patient)
Sources:
1200 mg 1 times / day steady, oral
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 60 years (range: 15-83 years)
n = 10
Health Status: unhealthy
Condition: Ph-positive ALL | CML
Age Group: 60 years (range: 15-83 years)
Sex: M+F
Population Size: 10
Sources:
Other AEs: Rash, Fatigue...
Other AEs:
Rash (grade 3-4, 3%)
Fatigue (grade 3-4, 3%)
Bilirubin total increased (grade 3-4, 3%)
Conjugated bilirubin level increased (grade 3-4, 3%)
Bilirubin unconjugated increased (grade 3-4, 6%)
Lipase increased (grade 3-4, 3%)
ALT increased (grade 3-4, 9%)
Aspartate aminotransferase increased (grade 3-4, 9%)
Thrombocytopenia (grade 3-4, 17%)
Neutropenia (grade 3-4, 14%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Neutropenia 1 patient
Disc. AE
400 mg 2 times / day steady, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: steady
Dose: 400 mg, 2 times / day
Sources:
unhealthy, 56 years (range: 26-85 years)
n = 132
Health Status: unhealthy
Condition: Philadelphia chromosome positive chronic myelogenous leukemia - chronic phase ((CML-CP)
Age Group: 56 years (range: 26-85 years)
Sex: M+F
Population Size: 132
Sources:
Skin rash 1 patient
Disc. AE
400 mg 2 times / day steady, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: steady
Dose: 400 mg, 2 times / day
Sources:
unhealthy, 56 years (range: 26-85 years)
n = 132
Health Status: unhealthy
Condition: Philadelphia chromosome positive chronic myelogenous leukemia - chronic phase ((CML-CP)
Age Group: 56 years (range: 26-85 years)
Sex: M+F
Population Size: 132
Sources:
Bilirubin increased 2 patients
Disc. AE
400 mg 2 times / day steady, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: steady
Dose: 400 mg, 2 times / day
Sources:
unhealthy, 56 years (range: 26-85 years)
n = 132
Health Status: unhealthy
Condition: Philadelphia chromosome positive chronic myelogenous leukemia - chronic phase ((CML-CP)
Age Group: 56 years (range: 26-85 years)
Sex: M+F
Population Size: 132
Sources:
Hepatotoxicity 2 patients
Disc. AE
400 mg 2 times / day steady, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: steady
Dose: 400 mg, 2 times / day
Sources:
unhealthy, 56 years (range: 26-85 years)
n = 132
Health Status: unhealthy
Condition: Philadelphia chromosome positive chronic myelogenous leukemia - chronic phase ((CML-CP)
Age Group: 56 years (range: 26-85 years)
Sex: M+F
Population Size: 132
Sources:
Thrombocytopenia 5 patients
Disc. AE
400 mg 2 times / day steady, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: steady
Dose: 400 mg, 2 times / day
Sources:
unhealthy, 56 years (range: 26-85 years)
n = 132
Health Status: unhealthy
Condition: Philadelphia chromosome positive chronic myelogenous leukemia - chronic phase ((CML-CP)
Age Group: 56 years (range: 26-85 years)
Sex: M+F
Population Size: 132
Sources:
Myocardial infarction 1 patient
Disc. AE
400 mg 2 times / day steady, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: steady
Dose: 400 mg, 2 times / day
Sources:
unhealthy, 59 years (range: 22-79 years)
n = 64
Health Status: unhealthy
Condition: Philadelphia chromosome positive chronic myelogenous leukemia - accelerated phase (CML-AP)
Age Group: 59 years (range: 22-79 years)
Sex: M+F
Population Size: 64
Sources:
Pancreatitis 1 patient
Disc. AE
400 mg 2 times / day steady, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: steady
Dose: 400 mg, 2 times / day
Sources:
unhealthy, 59 years (range: 22-79 years)
n = 64
Health Status: unhealthy
Condition: Philadelphia chromosome positive chronic myelogenous leukemia - accelerated phase (CML-AP)
Age Group: 59 years (range: 22-79 years)
Sex: M+F
Population Size: 64
Sources:
Rash 1 patient
Disc. AE
400 mg 2 times / day steady, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: steady
Dose: 400 mg, 2 times / day
Sources:
unhealthy, 59 years (range: 22-79 years)
n = 64
Health Status: unhealthy
Condition: Philadelphia chromosome positive chronic myelogenous leukemia - accelerated phase (CML-AP)
Age Group: 59 years (range: 22-79 years)
Sex: M+F
Population Size: 64
Sources:
Neutropenia grade 3, 1 patient
Disc. AE
400 mg 2 times / day steady, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: steady
Dose: 400 mg, 2 times / day
Sources:
unhealthy, 59 years (range: 22-79 years)
n = 64
Health Status: unhealthy
Condition: Philadelphia chromosome positive chronic myelogenous leukemia - accelerated phase (CML-AP)
Age Group: 59 years (range: 22-79 years)
Sex: M+F
Population Size: 64
Sources:
Thrombocytopenia grade 3, 1 patient
Disc. AE
400 mg 2 times / day steady, oral
Recommended
Dose: 400 mg, 2 times / day
Route: oral
Route: steady
Dose: 400 mg, 2 times / day
Sources:
unhealthy, 59 years (range: 22-79 years)
n = 64
Health Status: unhealthy
Condition: Philadelphia chromosome positive chronic myelogenous leukemia - accelerated phase (CML-AP)
Age Group: 59 years (range: 22-79 years)
Sex: M+F
Population Size: 64
Sources:
Neutropenia grade 3-4, 14%
1200 mg 1 times / day steady, oral
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 60 years (range: 15-83 years)
n = 10
Health Status: unhealthy
Condition: Ph-positive ALL | CML
Age Group: 60 years (range: 15-83 years)
Sex: M+F
Population Size: 10
Sources:
Thrombocytopenia grade 3-4, 17%
1200 mg 1 times / day steady, oral
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 60 years (range: 15-83 years)
n = 10
Health Status: unhealthy
Condition: Ph-positive ALL | CML
Age Group: 60 years (range: 15-83 years)
Sex: M+F
Population Size: 10
Sources:
Bilirubin total increased grade 3-4, 3%
1200 mg 1 times / day steady, oral
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 60 years (range: 15-83 years)
n = 10
Health Status: unhealthy
Condition: Ph-positive ALL | CML
Age Group: 60 years (range: 15-83 years)
Sex: M+F
Population Size: 10
Sources:
Conjugated bilirubin level increased grade 3-4, 3%
1200 mg 1 times / day steady, oral
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 60 years (range: 15-83 years)
n = 10
Health Status: unhealthy
Condition: Ph-positive ALL | CML
Age Group: 60 years (range: 15-83 years)
Sex: M+F
Population Size: 10
Sources:
Fatigue grade 3-4, 3%
1200 mg 1 times / day steady, oral
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 60 years (range: 15-83 years)
n = 10
Health Status: unhealthy
Condition: Ph-positive ALL | CML
Age Group: 60 years (range: 15-83 years)
Sex: M+F
Population Size: 10
Sources:
Lipase increased grade 3-4, 3%
1200 mg 1 times / day steady, oral
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 60 years (range: 15-83 years)
n = 10
Health Status: unhealthy
Condition: Ph-positive ALL | CML
Age Group: 60 years (range: 15-83 years)
Sex: M+F
Population Size: 10
Sources:
Rash grade 3-4, 3%
1200 mg 1 times / day steady, oral
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 60 years (range: 15-83 years)
n = 10
Health Status: unhealthy
Condition: Ph-positive ALL | CML
Age Group: 60 years (range: 15-83 years)
Sex: M+F
Population Size: 10
Sources:
Bilirubin unconjugated increased grade 3-4, 6%
1200 mg 1 times / day steady, oral
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 60 years (range: 15-83 years)
n = 10
Health Status: unhealthy
Condition: Ph-positive ALL | CML
Age Group: 60 years (range: 15-83 years)
Sex: M+F
Population Size: 10
Sources:
ALT increased grade 3-4, 9%
1200 mg 1 times / day steady, oral
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 60 years (range: 15-83 years)
n = 10
Health Status: unhealthy
Condition: Ph-positive ALL | CML
Age Group: 60 years (range: 15-83 years)
Sex: M+F
Population Size: 10
Sources:
Aspartate aminotransferase increased grade 3-4, 9%
1200 mg 1 times / day steady, oral
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 60 years (range: 15-83 years)
n = 10
Health Status: unhealthy
Condition: Ph-positive ALL | CML
Age Group: 60 years (range: 15-83 years)
Sex: M+F
Population Size: 10
Sources:
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
no
no
weak
yes [IC50 1.7 uM]
yes [Ki 0.132 uM]
yes [Ki 0.19 uM]
yes (pharmacogenomic study)
Comment: The (TA)7/(TA)7 genotype was associated with a statistically significant increase in risk of nilotinib-induced hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes.
yes [Ki 0.236 uM]
yes [Ki 0.448 uM]
yes (co-administration study)
Comment: nilotinib increased auc of midazolam by 30%
yes [Ki 1.46 uM]
yes [Ki 3.82 uM]
yes
yes
yes
yes
yes
yes
Drug as victimTox targets

Tox targets

PubMed

PubMed

TitleDatePubMed
Two new agents effective in Gleevec-resistant CML.
2004 Dec
After imatinib: new hopes for chronic myeloid leukaemia.
2005 Apr 15
In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants.
2005 Jun 1
Chronic myelogenous leukemia.
2005 Oct
[New strategies to overcome imatinib resistance in treatment for chronic myelocytic leukemia].
2006 Aug
Circumventing resistance to kinase-inhibitor therapy.
2006 Jun 15
Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.
2006 Jun 15
The FIP1L1-PDGFRA T674I mutation can be inhibited by the tyrosine kinase inhibitor AMN107 (nilotinib).
2006 Jun 15
The CML-related oncoprotein BCR/ABL induces expression of histidine decarboxylase (HDC) and the synthesis of histamine in leukemic cells.
2006 Nov 15
Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations.
2006 Oct 1
Identification of MCL1 as a novel target in neoplastic mast cells in systemic mastocytosis: inhibition of mast cell survival by MCL1 antisense oligonucleotides and synergism with PKC412.
2007 Apr 1
Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure.
2007 Apr 15
Centrosome aberrations after nilotinib and imatinib treatment in vitro are associated with mitotic spindle defects and genetic instability.
2007 Aug
Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors.
2007 Dec 1
[Molecular targeting therapy for chronic myeloid leukemia].
2007 Jan
Chronic Myeloid Leukaemia in The 21st Century.
2007 Jan
Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia.
2007 Jan
Successful allogeneic stem cell transplantation in second chronic-phase CML induced by the tyrosine kinase inhibitor nilotinib (AMN107) after blast crisis under imatinib.
2007 Jul
Gateways to clinical trials.
2007 Jun
[Novel anti-CML agents beyond imatinib].
2007 Jun
Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells.
2007 Jun
Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation.
2007 Mar 1
Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia.
2007 Oct 1
How I treat chronic myeloid leukemia in the imatinib era.
2007 Oct 15
Patents

Patents

Sample Use Guides

In Vivo Use Guide
Curator's Comment: 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.
400 mg orally twice daily, approximately 12 hours apart and should not be taken with food.
Route of Administration: Oral
AMN107 (nilotinib) inhibited proliferation of Ba/F3 cells expressing G250E, E255K(V), F317L, M351T, F486S, M244V, L248R, Q252H, Y253H, E255K, E279K, E282D, V289S, and L348M Bcr-Abl mutants at <1 uM concentrations.
Substance Class Chemical
Created
by admin
on Thu Jul 06 00:01:25 UTC 2023
Edited
by admin
on Thu Jul 06 00:01:25 UTC 2023
Record UNII
5JHU0N1R6K
Record Status Validated (UNII)
Record Version
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Name Type Language
NILOTINIB HYDROCHLORIDE MONOHYDRATE
ORANGE BOOK  
Common Name English
Nilotinib hydrochloride monohydrate [WHO-DD]
Common Name English
NILOTINIB HYDROCHLORIDE HYDRATE
JAN  
Common Name English
TASIGNA
Brand Name English
BENZAMIDE, 4-METHYL-N-(3-(4-METHYL-1H-IMIDAZOL-1-YL)-5-(TRIFLUOROMETHYL)PHENYL)-3-((4-(3-PYRIDINYL)-2-PYRIMIDINYL)AMINO)-, HYDROCHLORIDE, HYDRATE (1:1:1)
Systematic Name English
NILOTINIB HYDROCHLORIDE MONOHYDRATE [MI]
Common Name English
NILOTINIB HYDROCHLORIDE MONOHYDRATE [EP MONOGRAPH]
Common Name English
NILOTINIB HYDROCHLORIDE MONOHYDRATE [ORANGE BOOK]
Common Name English
NILOTINIB HYDROCHLORIDE HYDRATE [JAN]
Common Name English
Nilotinib hydrochloride [WHO-DD]
Common Name English
Classification Tree Code System Code
EU-Orphan Drug EU/3/07/447
Created by admin on Thu Jul 06 00:01:25 UTC 2023 , Edited by admin on Thu Jul 06 00:01:25 UTC 2023
NCI_THESAURUS C155700
Created by admin on Thu Jul 06 00:01:25 UTC 2023 , Edited by admin on Thu Jul 06 00:01:25 UTC 2023
EMA ASSESSMENT REPORTS TASIGNA (AUTHORIZED: LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE)
Created by admin on Thu Jul 06 00:01:25 UTC 2023 , Edited by admin on Thu Jul 06 00:01:25 UTC 2023
Code System Code Type Description
SMS_ID
100000091420
Created by admin on Thu Jul 06 00:01:25 UTC 2023 , Edited by admin on Thu Jul 06 00:01:25 UTC 2023
PRIMARY
FDA UNII
5JHU0N1R6K
Created by admin on Thu Jul 06 00:01:25 UTC 2023 , Edited by admin on Thu Jul 06 00:01:25 UTC 2023
PRIMARY
EPA CompTox
DTXSID00238967
Created by admin on Thu Jul 06 00:01:25 UTC 2023 , Edited by admin on Thu Jul 06 00:01:25 UTC 2023
PRIMARY
DRUG BANK
DBSALT001325
Created by admin on Thu Jul 06 00:01:25 UTC 2023 , Edited by admin on Thu Jul 06 00:01:25 UTC 2023
PRIMARY
EVMPD
SUB25647
Created by admin on Thu Jul 06 00:01:25 UTC 2023 , Edited by admin on Thu Jul 06 00:01:25 UTC 2023
PRIMARY
PUBCHEM
16757572
Created by admin on Thu Jul 06 00:01:25 UTC 2023 , Edited by admin on Thu Jul 06 00:01:25 UTC 2023
PRIMARY
CAS
923288-90-8
Created by admin on Thu Jul 06 00:01:25 UTC 2023 , Edited by admin on Thu Jul 06 00:01:25 UTC 2023
PRIMARY
NCI_THESAURUS
C95229
Created by admin on Thu Jul 06 00:01:25 UTC 2023 , Edited by admin on Thu Jul 06 00:01:25 UTC 2023
PRIMARY
ChEMBL
CHEMBL255863
Created by admin on Thu Jul 06 00:01:25 UTC 2023 , Edited by admin on Thu Jul 06 00:01:25 UTC 2023
PRIMARY
MERCK INDEX
M11754
Created by admin on Thu Jul 06 00:01:25 UTC 2023 , Edited by admin on Thu Jul 06 00:01:25 UTC 2023
PRIMARY
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