Nilotinib hydrobromide

Details

Stereochemistry	ACHIRAL
Molecular Formula	C28H22F3N7O.BrH
Molecular Weight	610.428
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

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

InChI

InChIKey=XBGUAPGMUHIVLC-UHFFFAOYSA-N

InChI=1S/C28H22F3N7O.BrH/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

HIDE SMILES / InChI

Molecular Formula	BrH
Molecular Weight	80.912
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

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022068lbl.pdf
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

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Bcr/Abl fusion protein 21 Target ID: CHEMBL2096618 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19920925	Inhibitor 8504		0.33 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) 13 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022068s023lbl.pdf	Primary		Approved 8583	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 2007

C_max

Value	Dose	Analyte	Population
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:
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:
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
2490 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	1200 mg 1 times / day steady-state, oral dose: 1200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
2190 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	800 mg 1 times / day steady-state, oral dose: 800 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
403 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	50 mg 1 times / day steady-state, oral dose: 50 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
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	Analyte	Population
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:
2795.782 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:
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:
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:
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:
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
28000 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	1200 mg 1 times / day steady-state, oral dose: 1200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
26600 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	800 mg 1 times / day steady-state, oral dose: 800 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
4480 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	50 mg 1 times / day steady-state, oral dose: 50 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
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

F_unbound

Value	Dose	Analyte	Population
2% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	1200 mg 1 times / day steady-state, oral dose: 1200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
2% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	800 mg 1 times / day steady-state, oral dose: 800 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
2% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	50 mg 1 times / day steady-state, oral dose: 50 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
1.6% OTHER GOV https://www.ema.europa.eu/en/documents/scientific-discussion/tasigna-epar-scientific-discussion_en.pdf		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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	unhealthy, 56 years (range: 26-85 years) Health Status: unhealthy Age Group: 56 years (range: 26-85 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf
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: https://pubmed.ncbi.nlm.nih.gov/19924121/	unhealthy, 56.2 ± 15.3 years Health Status: unhealthy Age Group: 56.2 ± 15.3 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/19924121/	Sources: https://pubmed.ncbi.nlm.nih.gov/19924121/
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	unhealthy, 59 years (range: 22-79 years) Health Status: unhealthy Age Group: 59 years (range: 22-79 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf
1200 mg 1 times / day steady, oral Dose: 1200 mg, 1 times / day Route: oral Route: steady Dose: 1200 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235	unhealthy, 60 years (range: 15-83 years) Health Status: unhealthy Age Group: 60 years (range: 15-83 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235	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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1087 substrate 1946	inducer 440 inhibitor 2438 substrate 1193	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A4/5 296 CYP2C8 1057 CYP2C19 2057 P-gp 1741 UGT1A1 246	P-gp 2052 MRP1 113 CYP2J2 71 CYP1A2 1197 CYP2C8 810 OCT1 393	CYP2B6 669 CYP2C8 198 CYP1A1 151 CYP1A2 832 UGT1A1 78 CYP2C19 329 P-gp 301 MRP2 146

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP2C19 2141	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	no
MRP2 625	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	no
P-gp 1932	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	no
UGT1A1 303	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	weak
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes [IC50 1.7 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes [Ki 0.132 uM]
UGT1A1 303	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	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. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes [Ki 0.236 uM]
CYP3A4/5 357	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes [Ki 0.448 uM]	yes (co-administration study) Comment: nilotinib increased auc of midazolam by 30% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes [Ki 1.46 uM]
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes [Ki 3.82 uM]
CYP1A1 272	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes
CYP1A2 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes
CYP2C8 1117	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes
CYP2C9 2497	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes
CYP3A4 2633	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	major	yes (co-administration study) Comment: ketoconazole increased auc of nilotinib by 3x, cmax by 84% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf
CYP1A2 1197	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	minor
CYP2C8 810	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	minor
CYP2C9 1193	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	minor
CYP2J2 71	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	minor
MRP1 113	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	no
OCT1 393	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	no
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_PharmR_P1.pdf

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:52172	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:52172
ChemicalBook	CB5966228	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB5966228
eMolecules	10645209	https://www.emolecules.com/cgi-bin/more?vid=10645209
MolPort	MolPort-003-987-089	https://www.molport.com/shop/molecule-link/MolPort-003-987-089
Selleck Chemicals	Nilotinib	http://www.selleckchem.com/products/Nilotinib.html
ZINC	ZINC000006716957	http://zinc15.docking.org/substances/ZINC000006716957

PubMed

Title	Date	PubMed
Loss of response to imatinib: mechanisms and management.	2005	16304378
Chronic myelogenous leukemia.	2005 Oct	16235580
The systemic mastocytosis-specific activating cKit mutation D816V can be inhibited by the tyrosine kinase inhibitor AMN107.	2005 Sep	16015383
[State of the art in the treatment of chronic leukemias].	2006 Apr	16715962
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	16614241
Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR-alpha-expressing cells.	2006 Dec	16682077
Novel treatment strategies for chronic myeloid leukemia.	2006 Dec 1	17106016
Looking beyond imatinib: next line of targeted drugs for CML shows promise.	2006 Jan 25	16434621
Circumventing resistance to kinase-inhibitor therapy.	2006 Jun 15	16775240
AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL.	2006 Jun 19	16721371
Kinase inhibitors in chronic myelogenous leukemia.	2006 May	16728945
Beyond imatinib: second generation c-KIT inhibitors for the management of gastrointestinal stromal tumors.	2006 Nov	17419150
BCR and its mutants, the reciprocal t(9;22)-associated ABL/BCR fusion proteins, differentially regulate the cytoskeleton and cell motility.	2006 Nov 7	17090304
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	16772610
Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure.	2007 Apr 15	17342766
Centrosome aberrations after nilotinib and imatinib treatment in vitro are associated with mitotic spindle defects and genetic instability.	2007 Aug	17614824
[Innovation of clinical trials for anti-cancer drugs in Japan--proposals from academia with special reference to the development of novel Bcr-Abl/Lyn tyrosine kinase inhibitor INNO-406 (NS-187) for imatinib-resistant chronic myelogenous leukemia].	2007 Feb	17301549
Important therapeutic targets in chronic myelogenous leukemia.	2007 Feb 15	17317816
[Molecular targeting therapy for chronic myeloid leukemia].	2007 Jan	17313076
New targeted therapies for chronic myelogenous leukemia: opportunities to overcome imatinib resistance.	2007 Jan	17292738
Drugs offer new hope for patients with CML who are resistant to imatinib.	2007 Jul	17694781
Monosomy 7 in t(9;22)-negative cells during nilotinib therapy in an imatinib-resistant chronic myeloid leukemia case.	2007 Jul 15	17656263
Novel tyrosine kinase inhibitor therapy before allogeneic stem cell transplantation in patients with chronic myeloid leukemia: no evidence for increased transplant-related toxicity.	2007 Jul 15	17559140
Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study.	2007 Jun 1	17303698
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	17090651
Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors.	2007 Nov	17403535
Synergistic antiproliferative effects of KIT tyrosine kinase inhibitors on neoplastic canine mast cells.	2007 Oct	17681669
Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency.	2007 Sep	17710227
The multikinase inhibitor sorafenib induces apoptosis in highly imatinib mesylate-resistant bcr/abl+ human leukemia cells in association with signal transducer and activator of transcription 5 inhibition and myeloid cell leukemia-1 down-regulation.	2007 Sep	17595328
Tyrosine kinase inhibitors for the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia.	2007 Sep 15	17701954

Patents

Sample Use Guides

In Vivo Use Guide

400 mg orally twice daily, approximately 12 hours apart and should not be taken with food.

Route of Administration: Oral

In Vitro Use Guide

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 `Wed Apr 02 20:10:58 GMT 2025` Edited by `admin` on `Wed Apr 02 20:10:58 GMT 2025`
Record UNII	BH3BS9EDA8
Record Status	`Validated (UNII)`
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Name

Type

Language

Benzamide, 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-, hydrobromide (1:1)

Preferred Name

English

Nilotinib hydrobromide

Common Name

English

Code System Code Type Description

FDA UNII

BH3BS9EDA8

Created by admin on Wed Apr 02 20:10:58 GMT 2025 , Edited by admin on Wed Apr 02 20:10:58 GMT 2025

PRIMARY

CAS

1353151-22-0

Created by admin on Wed Apr 02 20:10:58 GMT 2025 , Edited by admin on Wed Apr 02 20:10:58 GMT 2025

PRIMARY

PUBCHEM

56592675

Created by admin on Wed Apr 02 20:10:58 GMT 2025 , Edited by admin on Wed Apr 02 20:10:58 GMT 2025

PRIMARY

Related Record Type Details


					F41401512X

Nilotinib

PARENT -> SALT/SOLVATE

Amount:

Related Record Type Details


					F41401512X

Nilotinib

ACTIVE MOIETY

Amount:

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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	unhealthy, 56 years (range: 26-85 years) Health Status: unhealthy Age Group: 56 years (range: 26-85 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	unhealthy, 56 years (range: 26-85 years) Health Status: unhealthy Age Group: 56 years (range: 26-85 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	unhealthy, 56 years (range: 26-85 years) Health Status: unhealthy Age Group: 56 years (range: 26-85 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	unhealthy, 56 years (range: 26-85 years) Health Status: unhealthy Age Group: 56 years (range: 26-85 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	unhealthy, 56 years (range: 26-85 years) Health Status: unhealthy Age Group: 56 years (range: 26-85 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	unhealthy, 59 years (range: 22-79 years) Health Status: unhealthy Age Group: 59 years (range: 22-79 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	unhealthy, 59 years (range: 22-79 years) Health Status: unhealthy Age Group: 59 years (range: 22-79 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	unhealthy, 59 years (range: 22-79 years) Health Status: unhealthy Age Group: 59 years (range: 22-79 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	unhealthy, 59 years (range: 22-79 years) Health Status: unhealthy Age Group: 59 years (range: 22-79 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	unhealthy, 59 years (range: 22-79 years) Health Status: unhealthy Age Group: 59 years (range: 22-79 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235	unhealthy, 60 years (range: 15-83 years) Health Status: unhealthy Age Group: 60 years (range: 15-83 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235	unhealthy, 60 years (range: 15-83 years) Health Status: unhealthy Age Group: 60 years (range: 15-83 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235	unhealthy, 60 years (range: 15-83 years) Health Status: unhealthy Age Group: 60 years (range: 15-83 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235	unhealthy, 60 years (range: 15-83 years) Health Status: unhealthy Age Group: 60 years (range: 15-83 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235	unhealthy, 60 years (range: 15-83 years) Health Status: unhealthy Age Group: 60 years (range: 15-83 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235	unhealthy, 60 years (range: 15-83 years) Health Status: unhealthy Age Group: 60 years (range: 15-83 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235	unhealthy, 60 years (range: 15-83 years) Health Status: unhealthy Age Group: 60 years (range: 15-83 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235	unhealthy, 60 years (range: 15-83 years) Health Status: unhealthy Age Group: 60 years (range: 15-83 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235	unhealthy, 60 years (range: 15-83 years) Health Status: unhealthy Age Group: 60 years (range: 15-83 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235	unhealthy, 60 years (range: 15-83 years) Health Status: unhealthy Age Group: 60 years (range: 15-83 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235

Details

SMILES

InChI

DescriptionSources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022068lbl.pdfCurator'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

CNS Activity

Originator

Approval Year

Targets

Conditions

Approved Use

Launch Date

Cmax

AUC

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022068lbl.pdf
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

C_max

F_unbound

Drug as perpetrator