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Details

Stereochemistry ACHIRAL
Molecular Formula C20H15ClF3N5.ClH
Molecular Weight 454.276
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of PEXIDARTINIB HYDROCHLORIDE

SMILES

Cl.FC(F)(F)C1=NC=C(CNC2=NC=C(CC3=CNC4=C3C=C(Cl)C=N4)C=C2)C=C1

InChI

InChIKey=CJLUYLRKLUYCEK-UHFFFAOYSA-N
InChI=1S/C20H15ClF3N5.ClH/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);1H

HIDE SMILES / InChI
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)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
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: Page: p. 149
unhealthy, 44 years (range: 18-79 years)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
Sources: Page: p. 149
Disc. AE: Hypertension, LDH increased...
AEs leading to
discontinuation/dose reduction:
Hypertension (all grades, 1.6%)
LDH increased (all grades, 1.6%)
Sources: Page: p. 149
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)
n = 4
Health Status: unhealthy
Age Group: 60.6 years (range: 24-82 years)
Sex: M+F
Population Size: 4
Sources:
1000 mg 1 times / day steady, oral
MTD
unhealthy, 63 years (range: 40–82 years)
n = 8
Health Status: unhealthy
Age Group: 63 years (range: 40–82 years)
Sex: M+F
Population Size: 8
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
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)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
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)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
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)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
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)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
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)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
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)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
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)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
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)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
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)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
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)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
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)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
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)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
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: Page: p. 149
unhealthy, 44 years (range: 18-79 years)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
Sources: Page: p. 149
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: Page: p. 149
unhealthy, 44 years (range: 18-79 years)
n = 61
Health Status: unhealthy
Condition: symptomatic tenosynovial giant cell tumor
Age Group: 44 years (range: 18-79 years)
Sex: M+F
Population Size: 61
Sources: Page: p. 149
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
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.
Name Type Language
PEXIDARTINIB HYDROCHLORIDE
Common Name English
PEXIDARTINIB HYDROCHLORIDE [JAN]
Common Name English
PLX3397 HYDROCHLORIDE
Code English
PEXIDARTINIB HYDROCHLORIDE [USAN]
Common Name English
Pexidartinib hydrochloride [WHO-DD]
Common Name English
PLX-3397 HCL
Code English
PLX-3397 HYDROCHLORIDE
Code English
5-((5-CHLORO-1H-PYRROLO(2,3-B)PYRIDIN-3-YL)METHYL)-N-((6-(TRIFLUOROMETHYL)PYRIDIN-3-YL)METHYL)PYRIDIN-2-AMINE HYDROCHLORIDE
Systematic Name English
PLX3397 HCL
Code English
PEXIDARTINIB HYDROCHLORIDE [ORANGE BOOK]
Common Name English
(5-(5-CHLORO-1H-PYRROLO(2,3-B)PYRIDIN-3-YLMETHYL)-PYRIDIN-2-YL)-(6-TRIFLUOROMETHYL-PYRIDIN-3-YLMETHYL)-AMINE HYDROCHLORIDE SALT
Systematic Name English
Classification Tree Code System Code
FDA ORPHAN DRUG 419913
Created by admin on Fri Dec 15 16:16:53 GMT 2023 , Edited by admin on Fri Dec 15 16:16:53 GMT 2023
EU-Orphan Drug EU/3/15/1457
Created by admin on Fri Dec 15 16:16:53 GMT 2023 , Edited by admin on Fri Dec 15 16:16:53 GMT 2023
Code System Code Type Description
DRUG BANK
DBSALT002881
Created by admin on Fri Dec 15 16:16:53 GMT 2023 , Edited by admin on Fri Dec 15 16:16:53 GMT 2023
PRIMARY
SMS_ID
100000181878
Created by admin on Fri Dec 15 16:16:53 GMT 2023 , Edited by admin on Fri Dec 15 16:16:53 GMT 2023
PRIMARY
DAILYMED
YS6WAI3XN7
Created by admin on Fri Dec 15 16:16:53 GMT 2023 , Edited by admin on Fri Dec 15 16:16:53 GMT 2023
PRIMARY
EPA CompTox
DTXSID001026483
Created by admin on Fri Dec 15 16:16:53 GMT 2023 , Edited by admin on Fri Dec 15 16:16:53 GMT 2023
PRIMARY
USAN
EF-90
Created by admin on Fri Dec 15 16:16:53 GMT 2023 , Edited by admin on Fri Dec 15 16:16:53 GMT 2023
PRIMARY
NCI_THESAURUS
C170314
Created by admin on Fri Dec 15 16:16:53 GMT 2023 , Edited by admin on Fri Dec 15 16:16:53 GMT 2023
PRIMARY
CAS
2040295-03-0
Created by admin on Fri Dec 15 16:16:53 GMT 2023 , Edited by admin on Fri Dec 15 16:16:53 GMT 2023
PRIMARY
RXCUI
2183103
Created by admin on Fri Dec 15 16:16:53 GMT 2023 , Edited by admin on Fri Dec 15 16:16:53 GMT 2023
PRIMARY
FDA UNII
YS6WAI3XN7
Created by admin on Fri Dec 15 16:16:53 GMT 2023 , Edited by admin on Fri Dec 15 16:16:53 GMT 2023
PRIMARY
PUBCHEM
73053710
Created by admin on Fri Dec 15 16:16:53 GMT 2023 , Edited by admin on Fri Dec 15 16:16:53 GMT 2023
PRIMARY