Details
Stereochemistry | ACHIRAL |
Molecular Formula | C28H22F3N7O.ClH |
Molecular Weight | 565.977 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
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=VTGGYCCJUPYZSX-UHFFFAOYSA-N
InChI=1S/C28H22F3N7O.ClH/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
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 |
DescriptionCurator'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
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.
CNS Activity
Originator
Sources: https://www.ncbi.nlm.nih.gov/pubmed/15710326
Curator's Comment: # Novartis Pharmaceuticals Corporation
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2096618 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19920925 |
0.33 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | TASIGNA Approved UseTasigna 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 Date2007 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1550 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121 |
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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121 |
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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121 |
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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121 |
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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544 |
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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544 |
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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30179260 |
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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30179260 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
12700 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121 |
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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121 |
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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121 |
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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121 |
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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544 |
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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544 |
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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544 |
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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544 |
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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544 |
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 Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544 |
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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30179260 |
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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30179260 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1.6% |
NILOTINIB plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Doses
Dose | Population | Adverse 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) Sources: Neutropenia (1 patient) Bilirubin increased (2 patients) Hepatotoxicity (2 patients) Skin rash (1 patient) |
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) Sources: Pancreatitis (1 patient) Myocardial infarction (1 patient) Thrombocytopenia (grade 3, 1 patient) Neutropenia (grade 3, 1 patient) |
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%) Sources: 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%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
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: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical 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 victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
major | yes (co-administration study) Comment: ketoconazole increased auc of nilotinib by 3x, cmax by 84% |
|||
minor | ||||
minor | ||||
minor | ||||
minor | ||||
no | ||||
no | ||||
yes |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
PubMed
Title | Date | PubMed |
---|---|---|
Two new agents effective in Gleevec-resistant CML. | 2004 Dec |
|
[Novel inhibitors of Bcr-Abl]. | 2006 |
|
Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107). | 2006 Aug 15 |
|
Gateways to clinical trials. | 2006 Dec |
|
Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells. | 2006 Jul 15 |
|
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 |
|
AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. | 2006 Jun 19 |
|
Kinase inhibitors in chronic myelogenous leukemia. | 2006 May |
|
Novel tyrosine kinase inhibitors in chronic myelogenous leukemia. | 2006 Nov |
|
Effects of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, on human mast cells bearing wild-type or mutated codon 816 c-kit. | 2006 Nov |
|
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 |
|
[Molecular targeting therapy for chronic myeloid leukemia]. | 2007 Jan |
|
Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia. | 2007 Jan |
|
Drugs offer new hope for patients with CML who are resistant to imatinib. | 2007 Jul |
|
Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study. | 2007 Jun 1 |
|
Gateways to clinical trials. | 2007 Mar |
|
Bcr-Abl kinase domain mutations and the unsettled problem of Bcr-AblT315I: looking into the future of controlling drug resistance in chronic myeloid leukemia. | 2007 Mar |
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Emerging safety issues with imatinib and other Abl tyrosine kinase inhibitors. | 2007 Mar |
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Emerging strategies for the treatment of mutant Bcr-Abl T315I myeloid leukemia. | 2007 Mar |
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Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. | 2007 May 1 |
|
Crystal structure of the T315I mutant of AbI kinase. | 2007 Sep |
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
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/15710326
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
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