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
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
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.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL1936 |
0.027 µM [IC50] | ||
Target ID: CHEMBL1844 |
0.013 µM [IC50] | ||
Target ID: CHEMBL1974 |
0.16 µM [IC50] | ||
Target ID: CHEMBL6002 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26222558 |
0.14 µM [IC50] | ||
Target ID: CHEMBL279 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26222558 |
0.44 µM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | PEXIDARTINIB Approved UseUnknown |
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Primary | PEXIDARTINIB Approved UseUnknown |
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Primary | PEXIDARTINIB Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
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
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, 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%) Sources: 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%) |
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%) Sources: Page: p. 149LDH increased (all grades, 1.6%) |
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 Dose: 1000 mg, 1 times / day Route: oral Route: steady Dose: 1000 mg, 1 times / day Sources: |
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 Health Status: unhealthy Sources: |
Other AEs: Hepatotoxicity... Other AEs: Hepatotoxicity (grade 5) Sources: |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
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 Health Status: unhealthy Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical 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] | ||||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211810Orig1s000MultidisciplineR.pdf#page=101 Page: 67, 87-88 |
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. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211810Orig1s000MultidisciplineR.pdf#page=101 Page: 67, 87-88 |
||
yes | ||||
yes | ||||
yes | ||||
yes | ||||
yes | ||||
yes | ||||
yes | ||||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211810Orig1s000MultidisciplineR.pdf#page=101 Page: 67, 87-88 |
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. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211810Orig1s000MultidisciplineR.pdf#page=101 Page: 67, 87-88 |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211810Orig1s000MultidisciplineR.pdf#page=101 Page: 58, 62, 67, 68, 83-85 |
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). Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211810Orig1s000MultidisciplineR.pdf#page=101 Page: 58, 62, 67, 68, 83-85 |
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no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211810Orig1s000MultidisciplineR.pdf#page=97 Page: 83-85 |
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. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211810Orig1s000MultidisciplineR.pdf#page=97 Page: 83-85 |
||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211810Orig1s000MultidisciplineR.pdf#page=99 Page: 58, 62, 67, 68, 85-86 |
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). Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211810Orig1s000MultidisciplineR.pdf#page=99 Page: 58, 62, 67, 68, 85-86 |
||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211810Orig1s000MultidisciplineR.pdf#page=99 Page: 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. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211810Orig1s000MultidisciplineR.pdf#page=99 Page: 85-86 |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211810Orig1s000MultidisciplineR.pdf#page=39 Page: 25, 32, 39, 78 |
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 Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/28572167
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.
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Classification Tree | Code System | Code | ||
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FDA ORPHAN DRUG |
419913
Created by
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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
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DBSALT002881
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100000181878
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YS6WAI3XN7
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DTXSID001026483
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EF-90
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C170314
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2040295-03-0
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2183103
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YS6WAI3XN7
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73053710
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ACTIVE MOIETY
SUBSTANCE RECORD