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Details

Stereochemistry ACHIRAL
Molecular Formula C20H15ClF3N5
Molecular Weight 417.8155
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of PEXIDARTINIB

SMILES

c1cc(C(F)(F)F)ncc1CNc2ccc(Cc3c[nH]c4c3cc(cn4)Cl)cn2

InChI

InChIKey=JGWRKYUXBBNENE-UHFFFAOYSA-N
InChI=1S/C20H15ClF3N5/c21-15-6-16-14(10-28-19(16)29-11-15)5-12-2-4-18(26-7-12)27-9-13-1-3-17(25-8-13)20(22,23)24/h1-4,6-8,10-11H,5,9H2,(H,26,27)(H,28,29)

HIDE SMILES / InChI

Molecular Formula C20H15ClF3N5
Molecular Weight 417.8155
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Pexidartinib (PLX3397) is a small-molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Pexidartinib binds to and inhibits phosphorylation of stem cell factor receptor (KIT), colony-stimulating factor-1 receptor (CSF1R) and FMS-like tyrosine kinase 3 (FLT3), which may result in the inhibition of tumor cell proliferation and down-modulation of macrophages, osteoclasts and mast cells involved in the osteolytic metastatic disease. FDA has granted Breakthrough Therapy Designation to pexidartinib (PLX3397) for the treatment of tenosynovial giant cell tumor (TGCT) where surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. In addition to Breakthrough Therapy Designation, pexidartinib (PLX3397) has been granted Orphan Drug Designation by FDA for the treatment of pigmented villonodular synovitis (PVNS) and giant cell tumor of the tendon sheath (GCT-TS). It also has received Orphan Designation from the European Commission for the treatment of TGCT.

Approval Year

TargetsConditions
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
8625 ng/mL
400 mg 2 times / day steady-state, oral
dose: 400 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
PEXIDARTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
77465 ng × h/mL
400 mg 2 times / day steady-state, oral
dose: 400 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
PEXIDARTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
26.6 h
400 mg 2 times / day steady-state, oral
dose: 400 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
PEXIDARTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
1%
400 mg 2 times / day steady-state, oral
dose: 400 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
PEXIDARTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
Disc. AE: ALT increased, AST increased...
AEs leading to
discontinuation/dose reduction:
ALT increased (all grades, 4.9%)
AST increased (all grades, 4.9%)
Hepatotoxicity (all grades, 3.3%)
ALT increased (all grades, 13%)
AST increased (all grades, 13%)
Nausea (all grades, 8%)
ALP increased (all grades, 7%)
Vomiting (all grades, 4.9%)
Bilirubin increased (all grades, 3.3%)
GGT increased (all grades, 3.3%)
Dizziness (3.3%)
Abdominal pain (3.3%)
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
Disc. AE: Hypertension, LDH increased...
AEs leading to
discontinuation/dose reduction:
Hypertension (all grades, 1.6%)
LDH increased (all grades, 1.6%)
Sources:
5000 mg 1 times / day multiple, oral
Studied dose
Dose: 5000 mg, 1 times / day
Route: oral
Route: multiple
Dose: 5000 mg, 1 times / day
Sources:
unhealthy, 60.6 years (range: 24-82 years)
Health Status: unhealthy
Age Group: 60.6 years (range: 24-82 years)
Sex: M+F
Sources:
1000 mg 1 times / day steady, oral
MTD
unhealthy, 63 years (range: 40–82 years)
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
Other AEs: Hepatotoxicity...
AEs

AEs

AESignificanceDosePopulation
Abdominal pain 3.3%
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
Dizziness 3.3%
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
ALT increased all grades, 13%
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
AST increased all grades, 13%
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
Bilirubin increased all grades, 3.3%
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
GGT increased all grades, 3.3%
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
Hepatotoxicity all grades, 3.3%
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
ALT increased all grades, 4.9%
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
AST increased all grades, 4.9%
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
Vomiting all grades, 4.9%
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
ALP increased all grades, 7%
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
Nausea all grades, 8%
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
Hypertension all grades, 1.6%
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
LDH increased all grades, 1.6%
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, 44 years (range: 18-79 years)
Health Status: unhealthy
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Sources:
Hepatotoxicity grade 5
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
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
no
no
weak
yes [IC50 16.7 uM]
yes [IC50 22 uM]
yes [IC50 26 uM]
yes [IC50 3.7 uM]
yes [IC50 6.9 uM]
yes [IC50 7.9 uM]
yes [IC50 9.3 uM]
yes [IC50 9.3 uM]
unlikely (co-administration study)
Comment: Estimated IC50; Coadministration of pexidartinib decreased the geometric mean Cmax and AUC0-inf of omeprazole (a CYP2C19 substrate) by 37% and 17%, respectively. Comparable decreases in geometric mean Cmax (decrease by 36%) and AUC0-inf (decrease by 23%) were observed for 5-hydroxy omeprazole resulting in similar M/P ratio (73% (OME alone) vs. 72% (OME + Pexidartinib)). The observed similar M/P ratio indicates that pexidartinib had no impact on the CYP2C19 pathway.
Page: 67, 87-88
yes
yes
yes
yes
yes
yes
yes
yes
likely (co-administration study)
Comment: Coadministration of pexidartinib increased the geometric mean Cmax of digoxin (a P-gp substrate) by 32% with no effect on its AUC0-inf (only 9% increase). The increase in digoxin Cmax is consistent with P-gp inhibitory effect of pexidartinib in the gut.
Page: 67, 87-88
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
major
yes (co-administration study)
Comment: 76 % metabolized by CYP3A4; Itraconazole, a strong CYP3A4 inhibitor (200 mg loading dose then 200 mg once daily for 15 days) increased the geometric mean AUC0-inf and Cmax of pexidartinib by 73% and 48%. Rifampin, a strong CYP3A4 inducer (600 mg once daily for 10 days) reduced the geometric mean AUC0-inf and Cmax of pexidartinib by 63% and 33%, respectively, compared to pexidartinib alone (600 mg single dose).
Page: 58, 62, 67, 68, 83-85
no
no
no
no
no
no
no
no
no
no
yes
yes (co-administration study)
Comment: Coadministration of itraconazole (strong CYP3A4 inhibitor) increased the geometric mean Cmax and AUC0-inf of ZAAD-1006a by 50% and 97%, respectively. Coadministration of rifampin (strong CYP3A4 inducer) decreased the geometric mean AUC0-inf of ZAAD-1006a by 45%, but increased its Cmax by 35% compared to pexidartinib alone.
Page: 83-85
yes
yes (co-administration study)
Comment: 25 % metabolized by UGT1A4; Probenecid, a known UGT inhibitor (500 mg four times a day) increased the geometric mean AUC0-inf of pexidartinib by 60% compared to pexidartinib alone (600 mg single dose) with no effect noted on its Cmax (only 5 % increase).
Page: 58, 62, 67, 68, 85-86
yes
yes (co-administration study)
Comment: Coadministration of probenecid (UGT inhibitor) increased the geometric mean AUC0-inf of ZAAD-1006a by 125% with no effect on Cmax (1% decrease) compared to pexidartinib alone.
Page: 85-86
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Translocation and expression of CSF1 in pigmented villonodular synovitis, tenosynovial giant cell tumor, rheumatoid arthritis and other reactive synovitides.
2007 Jun
Molecular pathways involved in synovial cell inflammation and tumoral proliferation in diffuse pigmented villonodular synovitis.
2010 Sep
Synovial colony-stimulating factor-1 mRNA expression in diffuse pigmented villonodular synovitis.
2011 May-Jun
Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor.
2015 Jul 30
Colony-Stimulating Factor 1 Receptor Blockade Inhibits Tumor Growth by Altering the Polarization of Tumor-Associated Macrophages in Hepatocellular Carcinoma.
2017 Aug
Patents

Sample Use Guides

1000 mg per day for 2 weeks (dose split over morning and evening), then 800 mg per day for 22 weeks (dose split over morning and evening).
Route of Administration: Oral
In vitro, a population doubling assay showed that the IC50 of pexidartinib (PLX3397) for CSF1-induced bone marrow–derived macrophages (M(CSF1)) was 22 nM. Marked suppression of CSF-1R phosphorylation in M(CSF1) cells could be achieved with PLX3397. In contrast, the same doses of PLX3397 showed no antiproliferation effect on Hepa1-6, MHCC97-H, HCCLM3, HepG2, HUVEC, T cells, fibroblasts cells, and CSF2-induced bone marrow–derived macrophages.
Substance Class Chemical
Created
by admin
on Sat Jun 26 10:28:01 UTC 2021
Edited
by admin
on Sat Jun 26 10:28:01 UTC 2021
Record UNII
6783M2LV5X
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
PEXIDARTINIB
INN   WHO-DD  
INN  
Official Name English
PEXIDARTINIB [INN]
Common Name English
PLX3397
Code English
PLX-3397
Code English
PEXIDARTINIB [USAN]
Common Name English
PEXIDARTINIB [WHO-DD]
Common Name English
PEXIDARTINIB [MI]
Common Name English
CML-261
Code English
5-((5-CHLORO-1H-PYRROLO(2,3-B)PYRIDIN-3-YL)METHYL)-N-((6-(TRIFLUOROMETHYL)PYRIDIN-3-YL)METHYL)PYRIDIN-2-AMINE
Systematic Name English
3-PYRIDINEMETHANAMINE, N-(5-((5-CHLORO-1H-PYRROLO(2,3-B)PYRIDIN-3-YL)METHYL)-2-PYRIDINYL)-6-(TRIFLUOROMETHYL)-
Systematic Name English
Classification Tree Code System Code
NCI_THESAURUS C129825
Created by admin on Sat Jun 26 10:28:01 UTC 2021 , Edited by admin on Sat Jun 26 10:28:01 UTC 2021
NCI_THESAURUS C1967
Created by admin on Sat Jun 26 10:28:01 UTC 2021 , Edited by admin on Sat Jun 26 10:28:01 UTC 2021
Code System Code Type Description
ChEMBL
CHEMBL3545158
Created by admin on Sat Jun 26 10:28:01 UTC 2021 , Edited by admin on Sat Jun 26 10:28:01 UTC 2021
PRIMARY
CAS
1029044-16-3
Created by admin on Sat Jun 26 10:28:01 UTC 2021 , Edited by admin on Sat Jun 26 10:28:01 UTC 2021
PRIMARY
INN
10056
Created by admin on Sat Jun 26 10:28:01 UTC 2021 , Edited by admin on Sat Jun 26 10:28:01 UTC 2021
PRIMARY
DRUG BANK
DB12978
Created by admin on Sat Jun 26 10:28:01 UTC 2021 , Edited by admin on Sat Jun 26 10:28:01 UTC 2021
PRIMARY
PUBCHEM
25151352
Created by admin on Sat Jun 26 10:28:01 UTC 2021 , Edited by admin on Sat Jun 26 10:28:01 UTC 2021
PRIMARY
LACTMED
Pexidartinib
Created by admin on Sat Jun 26 10:28:01 UTC 2021 , Edited by admin on Sat Jun 26 10:28:01 UTC 2021
PRIMARY
MERCK INDEX
M12153
Created by admin on Sat Jun 26 10:28:01 UTC 2021 , Edited by admin on Sat Jun 26 10:28:01 UTC 2021
PRIMARY
NCI_THESAURUS
C88303
Created by admin on Sat Jun 26 10:28:01 UTC 2021 , Edited by admin on Sat Jun 26 10:28:01 UTC 2021
PRIMARY
RXCUI
2183102
Created by admin on Sat Jun 26 10:28:01 UTC 2021 , Edited by admin on Sat Jun 26 10:28:01 UTC 2021
PRIMARY
CAS
1447274-99-8
Created by admin on Sat Jun 26 10:28:01 UTC 2021 , Edited by admin on Sat Jun 26 10:28:01 UTC 2021
NO STRUCTURE GIVEN
DRUG CENTRAL
5343
Created by admin on Sat Jun 26 10:28:01 UTC 2021 , Edited by admin on Sat Jun 26 10:28:01 UTC 2021
PRIMARY
FDA UNII
6783M2LV5X
Created by admin on Sat Jun 26 10:28:01 UTC 2021 , Edited by admin on Sat Jun 26 10:28:01 UTC 2021
PRIMARY
Related Record Type Details
METABOLIC ENZYME -> INHIBITOR
IC50
METABOLIC ENZYME -> INDUCER
TARGET -> INHIBITOR
IC50
METABOLIC ENZYME -> INHIBITOR
IC50
METABOLIC ENZYME -> INHIBITOR
IC50
METABOLIC ENZYME -> INHIBITOR
IC50
TARGET -> INHIBITOR
IC50
LIGAND->BINDER
BINDING
METABOLIC ENZYME -> INHIBITOR
IC50
METABOLIC ENZYME -> INHIBITOR
IC50
METABOLIC ENZYME -> SUBSTRATE
METABOLIC ENZYME -> INDUCER
The induction of CYP3A4 enzyme (3.9 times) was lower than the mRNA increase (65 times), indicating possible time-dependent inhibition.
SALT/SOLVATE -> PARENT
METABOLIC ENZYME -> INHIBITOR
IC50
METABOLIC ENZYME -> INHIBITOR
IC50
EXCRETED UNCHANGED
AMOUNT EXCRETED
FECAL
METABOLIC ENZYME -> SUBSTRATE
SALT/SOLVATE -> PARENT
Related Record Type Details
ACTIVE MOIETY
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Volume of Distribution PHARMACOKINETIC ORAL ADMINISTRATION

SINGLE DOSE

IN HEALTHY SUBJECTS

Tmax PHARMACOKINETIC IN HEALTHY SUBJECTS

ORAL ADMINISTRATION

SINGLE DOSE

Biological Half-life PHARMACOKINETIC IN HEALTHY SUBJECTS

SINGLE DOSE

ORAL ADMINISTRATION