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Details

Stereochemistry ACHIRAL
Molecular Formula C23H26FN6O9P
Molecular Weight 580.4604
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of FOSTAMATINIB

SMILES

CC1(C)C(=O)N(COP(=O)(O)O)c2c(ccc(=Nc3c(cnc(Nc4cc(c(c(c4)OC)OC)OC)n3)F)[nH]2)O1

InChI

InChIKey=GKDRMWXFWHEQQT-UHFFFAOYSA-N
InChI=1S/C23H26FN6O9P/c1-23(2)21(31)30(11-38-40(32,33)34)20-14(39-23)6-7-17(28-20)27-19-13(24)10-25-22(29-19)26-12-8-15(35-3)18(37-5)16(9-12)36-4/h6-10H,11H2,1-5H3,(H2,32,33,34)(H2,25,26,27,28,29)

HIDE SMILES / InChI

Molecular Formula C23H26FN6O9P
Molecular Weight 580.4604
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Fostamatinib is a pro-drug of a Syk inhibitor R406 initially developed by Rigel Pharmaceuticals, but then in-licensed by AstraZeneca. It reached phase III of clinical trials for such diseases as Rheumatoid Arthritis and Immune Thrombocytopenic Purpura, however, AstraZeneca decided not to proceed with regulatory filings and return the rights to the compound to Rigel Pharmaceuticals. In 2018 the drug was approved by the FDA for treatment of chronic immune thrombocytopenia. Fostamatinib is being developed for Autoimmune Hemolytic Anemia (phase II), graft versus host disease (phase I) and ovarian cancer (phase I).

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
41.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Tavalisse

Approved Use

TAVALISSE is a kinase inhibitor indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

Launch Date

1.52383678E12
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
605 ng/mL
75 mg single, oral
dose: 75 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
R406 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
6490 ng × h/mL
75 mg single, oral
dose: 75 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
R406 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
17.9 h
75 mg single, oral
dose: 75 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
R406 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
Doses

Doses

DosePopulationAdverse events​
200 mg 2 times / day multiple, oral
Highest studied dose
Dose: 200 mg, 2 times / day
Route: oral
Route: multiple
Dose: 200 mg, 2 times / day
Sources:
unhealthy, 34-82 years
n = 7
Health Status: unhealthy
Age Group: 34-82 years
Sex: M+F
Population Size: 7
Sources:
Other AEs: Lymphopenia, Hypertension...
Other AEs:
Lymphopenia (grade 3-5, 14%)
Hypertension (grade 3-5, 29%)
Aspartate aminotransferase increased (grade 3-5, 14%)
Alkaline phosphatase increased (grade 3-5, 29%)
Hyperbilirubinemia (grade 3-5, 14%)
Anemia (grade 1-2, 29%)
Leukopenia (grade 1-2, 57%)
Neutropenia (grade 1-2, 14%)
Thrombocytopenia (grade 1-2, 29%)
Diarrhea (grade 1-2, 14%)
Fatigue (grade 1-2, 14%)
ALT increased (grade 1-2, 71%)
Sources:
260 mg 1 times / day multiple, oral (median)
Dose: 260 mg, 1 times / day
Route: oral
Route: multiple
Dose: 260 mg, 1 times / day
Sources: Page: p. 166
unhealthy, 53.5 years (range: 20 - 88 years)
n = 102
Health Status: unhealthy
Age Group: 53.5 years (range: 20 - 88 years)
Sex: M+F
Population Size: 102
Sources: Page: p. 166
Disc. AE: Abdominal pain, ALT increased...
AEs leading to
discontinuation/dose reduction:
Abdominal pain (1%)
ALT increased (1%)
Chest pain (1%)
Headache (1%)
Neutropenia (1%)
Pneumonia (1%)
Plasma cell myeloma (1%)
Syncope (1%)
Thrombocytopenia (1%)
Sources: Page: p. 166
AEs

AEs

AESignificanceDosePopulation
Diarrhea grade 1-2, 14%
200 mg 2 times / day multiple, oral
Highest studied dose
Dose: 200 mg, 2 times / day
Route: oral
Route: multiple
Dose: 200 mg, 2 times / day
Sources:
unhealthy, 34-82 years
n = 7
Health Status: unhealthy
Age Group: 34-82 years
Sex: M+F
Population Size: 7
Sources:
Fatigue grade 1-2, 14%
200 mg 2 times / day multiple, oral
Highest studied dose
Dose: 200 mg, 2 times / day
Route: oral
Route: multiple
Dose: 200 mg, 2 times / day
Sources:
unhealthy, 34-82 years
n = 7
Health Status: unhealthy
Age Group: 34-82 years
Sex: M+F
Population Size: 7
Sources:
Neutropenia grade 1-2, 14%
200 mg 2 times / day multiple, oral
Highest studied dose
Dose: 200 mg, 2 times / day
Route: oral
Route: multiple
Dose: 200 mg, 2 times / day
Sources:
unhealthy, 34-82 years
n = 7
Health Status: unhealthy
Age Group: 34-82 years
Sex: M+F
Population Size: 7
Sources:
Anemia grade 1-2, 29%
200 mg 2 times / day multiple, oral
Highest studied dose
Dose: 200 mg, 2 times / day
Route: oral
Route: multiple
Dose: 200 mg, 2 times / day
Sources:
unhealthy, 34-82 years
n = 7
Health Status: unhealthy
Age Group: 34-82 years
Sex: M+F
Population Size: 7
Sources:
Thrombocytopenia grade 1-2, 29%
200 mg 2 times / day multiple, oral
Highest studied dose
Dose: 200 mg, 2 times / day
Route: oral
Route: multiple
Dose: 200 mg, 2 times / day
Sources:
unhealthy, 34-82 years
n = 7
Health Status: unhealthy
Age Group: 34-82 years
Sex: M+F
Population Size: 7
Sources:
Leukopenia grade 1-2, 57%
200 mg 2 times / day multiple, oral
Highest studied dose
Dose: 200 mg, 2 times / day
Route: oral
Route: multiple
Dose: 200 mg, 2 times / day
Sources:
unhealthy, 34-82 years
n = 7
Health Status: unhealthy
Age Group: 34-82 years
Sex: M+F
Population Size: 7
Sources:
ALT increased grade 1-2, 71%
200 mg 2 times / day multiple, oral
Highest studied dose
Dose: 200 mg, 2 times / day
Route: oral
Route: multiple
Dose: 200 mg, 2 times / day
Sources:
unhealthy, 34-82 years
n = 7
Health Status: unhealthy
Age Group: 34-82 years
Sex: M+F
Population Size: 7
Sources:
Aspartate aminotransferase increased grade 3-5, 14%
200 mg 2 times / day multiple, oral
Highest studied dose
Dose: 200 mg, 2 times / day
Route: oral
Route: multiple
Dose: 200 mg, 2 times / day
Sources:
unhealthy, 34-82 years
n = 7
Health Status: unhealthy
Age Group: 34-82 years
Sex: M+F
Population Size: 7
Sources:
Hyperbilirubinemia grade 3-5, 14%
200 mg 2 times / day multiple, oral
Highest studied dose
Dose: 200 mg, 2 times / day
Route: oral
Route: multiple
Dose: 200 mg, 2 times / day
Sources:
unhealthy, 34-82 years
n = 7
Health Status: unhealthy
Age Group: 34-82 years
Sex: M+F
Population Size: 7
Sources:
Lymphopenia grade 3-5, 14%
200 mg 2 times / day multiple, oral
Highest studied dose
Dose: 200 mg, 2 times / day
Route: oral
Route: multiple
Dose: 200 mg, 2 times / day
Sources:
unhealthy, 34-82 years
n = 7
Health Status: unhealthy
Age Group: 34-82 years
Sex: M+F
Population Size: 7
Sources:
Alkaline phosphatase increased grade 3-5, 29%
200 mg 2 times / day multiple, oral
Highest studied dose
Dose: 200 mg, 2 times / day
Route: oral
Route: multiple
Dose: 200 mg, 2 times / day
Sources:
unhealthy, 34-82 years
n = 7
Health Status: unhealthy
Age Group: 34-82 years
Sex: M+F
Population Size: 7
Sources:
Hypertension grade 3-5, 29%
200 mg 2 times / day multiple, oral
Highest studied dose
Dose: 200 mg, 2 times / day
Route: oral
Route: multiple
Dose: 200 mg, 2 times / day
Sources:
unhealthy, 34-82 years
n = 7
Health Status: unhealthy
Age Group: 34-82 years
Sex: M+F
Population Size: 7
Sources:
ALT increased 1%
Disc. AE
260 mg 1 times / day multiple, oral (median)
Dose: 260 mg, 1 times / day
Route: oral
Route: multiple
Dose: 260 mg, 1 times / day
Sources: Page: p. 166
unhealthy, 53.5 years (range: 20 - 88 years)
n = 102
Health Status: unhealthy
Age Group: 53.5 years (range: 20 - 88 years)
Sex: M+F
Population Size: 102
Sources: Page: p. 166
Abdominal pain 1%
Disc. AE
260 mg 1 times / day multiple, oral (median)
Dose: 260 mg, 1 times / day
Route: oral
Route: multiple
Dose: 260 mg, 1 times / day
Sources: Page: p. 166
unhealthy, 53.5 years (range: 20 - 88 years)
n = 102
Health Status: unhealthy
Age Group: 53.5 years (range: 20 - 88 years)
Sex: M+F
Population Size: 102
Sources: Page: p. 166
Chest pain 1%
Disc. AE
260 mg 1 times / day multiple, oral (median)
Dose: 260 mg, 1 times / day
Route: oral
Route: multiple
Dose: 260 mg, 1 times / day
Sources: Page: p. 166
unhealthy, 53.5 years (range: 20 - 88 years)
n = 102
Health Status: unhealthy
Age Group: 53.5 years (range: 20 - 88 years)
Sex: M+F
Population Size: 102
Sources: Page: p. 166
Headache 1%
Disc. AE
260 mg 1 times / day multiple, oral (median)
Dose: 260 mg, 1 times / day
Route: oral
Route: multiple
Dose: 260 mg, 1 times / day
Sources: Page: p. 166
unhealthy, 53.5 years (range: 20 - 88 years)
n = 102
Health Status: unhealthy
Age Group: 53.5 years (range: 20 - 88 years)
Sex: M+F
Population Size: 102
Sources: Page: p. 166
Neutropenia 1%
Disc. AE
260 mg 1 times / day multiple, oral (median)
Dose: 260 mg, 1 times / day
Route: oral
Route: multiple
Dose: 260 mg, 1 times / day
Sources: Page: p. 166
unhealthy, 53.5 years (range: 20 - 88 years)
n = 102
Health Status: unhealthy
Age Group: 53.5 years (range: 20 - 88 years)
Sex: M+F
Population Size: 102
Sources: Page: p. 166
Plasma cell myeloma 1%
Disc. AE
260 mg 1 times / day multiple, oral (median)
Dose: 260 mg, 1 times / day
Route: oral
Route: multiple
Dose: 260 mg, 1 times / day
Sources: Page: p. 166
unhealthy, 53.5 years (range: 20 - 88 years)
n = 102
Health Status: unhealthy
Age Group: 53.5 years (range: 20 - 88 years)
Sex: M+F
Population Size: 102
Sources: Page: p. 166
Pneumonia 1%
Disc. AE
260 mg 1 times / day multiple, oral (median)
Dose: 260 mg, 1 times / day
Route: oral
Route: multiple
Dose: 260 mg, 1 times / day
Sources: Page: p. 166
unhealthy, 53.5 years (range: 20 - 88 years)
n = 102
Health Status: unhealthy
Age Group: 53.5 years (range: 20 - 88 years)
Sex: M+F
Population Size: 102
Sources: Page: p. 166
Syncope 1%
Disc. AE
260 mg 1 times / day multiple, oral (median)
Dose: 260 mg, 1 times / day
Route: oral
Route: multiple
Dose: 260 mg, 1 times / day
Sources: Page: p. 166
unhealthy, 53.5 years (range: 20 - 88 years)
n = 102
Health Status: unhealthy
Age Group: 53.5 years (range: 20 - 88 years)
Sex: M+F
Population Size: 102
Sources: Page: p. 166
Thrombocytopenia 1%
Disc. AE
260 mg 1 times / day multiple, oral (median)
Dose: 260 mg, 1 times / day
Route: oral
Route: multiple
Dose: 260 mg, 1 times / day
Sources: Page: p. 166
unhealthy, 53.5 years (range: 20 - 88 years)
n = 102
Health Status: unhealthy
Age Group: 53.5 years (range: 20 - 88 years)
Sex: M+F
Population Size: 102
Sources: Page: p. 166
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG



Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
no
yes
yes
no (co-administration study)
Comment: Coadministration of fostamatinib (100 mg BID x 8 days) decreased mean Cmax of pioglitazone and hydroxypioglitazone by 117% and 9%. The mean AUC was increased by 18% and decreased 10% for pioglitazone (AUC(0-inf)) and hydroxypioglitazone (AUC(0-48hr)), respectively. No dose modification of fostamatinib is needed when co-administering with CYP2C8 substrates.
Page: 68, 78
yes
yes (co-administration study)
Comment: Coadministration of fostamatinib (100 mg BID x 9 days) increased mean rosuvastatin (20 mg on Day 6) Cmax by 88% and mean AUC(0-inf) by 96%. Monitor for toxicities that may require dosage reduction of BCRP substrates (such as, rosuvastatin) when co-administering with fostamatinib.
Page: 68, 78-79
yes
yes (co-administration study)
Comment: Coadministration of fostamatinib (100 mg BID x 6 days) increased mean midazolam (7.5 mg on Day 7) Cmax by 9% and mean AUC(0-inf) by 25%. Coadministration of fostamatinib (100 mg BID x 7 days) increased mean Cmax of simvastatin (40mg on Day 6) and simvastatin acid by 113% and 83% and mean AUC(0-inf) by 64% and 66%.
Page: 68, 77-78
yes
yes (co-administration study)
Comment: Coadministration of fostamatinib (100 mg BID on Day 9 to Day 15) increased mean Cmax,ss of digoxin (a loading dose of 0.25 mg BID on Day 1 and 0.25 mg QD on Day 2 to Day 15) by 70% and mean AUCss by 37%. Monitor for toxicities that may require dosage reduction of P-gp substrates (such as, digoxin) when co-administering with fostamatinib.
Page: 68, 79
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
major
major
major
yes (co-administration study)
Comment: The AUC(0-inf) and Cmax of R406 (Fostamatinib 80mg, 2 hr after the 2nd dose of ketoconazole) was increased by 102% and 37% when fostamatinib was co-administered with ketoconazole (200 mg BID x 7 days, strong CYP3A4 inhibitor). The mean terminal t1/2 increased from 14 hr to 18 hr. Co-administration of verapamil (80 mg TID x 4 days, moderate CYP3A4 inhibitor) increased mean Cmax of R406 (fostamatinib 150 mg on the 2nd day w/verapamil) by 6% and mean AUC(0-inf) by 39%. The mean terminal t1/2 increased from 14 hours to 19 hours. Avoid concomitant use of strong CYP3A inducer due to the concern of loss of efficacy as the mean AUC(0-inf) of R406 (fostamatinib 150 mg on Day 6) was decreased by 75% and Cmax by 59% when fostamatinib was co-administration with rifampicin (600 mg QD x 8 days, strong CYP3A4 inducer).
Page: 64, 68, 75, 76
no
no
no
no
yes
Tox targets

Tox targets

Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation.
2006 Dec
Metabolism of fostamatinib, the oral methylene phosphate prodrug of the spleen tyrosine kinase inhibitor R406 in humans: contribution of hepatic and gut bacterial processes to the overall biotransformation.
2010 Jul
Patents

Sample Use Guides

Rheumatoid Arthritis: 100 mg twice daily or 150 mg once daily. Immune Thrombocytopenic Purpura: 100 mg or 150 mg twice daily for 24 weeks. IGA Nephropathy: 100 mg or 150 mg twice daily for 15 months. Autoimmune Hemolytic Anemia: 100 mg or 150 mg twice daily for 12 weeks.
Route of Administration: Oral
In primary human B cells, active metabolite of fostamatinib, R406, inhibited CD69 up-regulation in response to anti-IgM with an EC50 of 48 nM. EC50 for IgE-induced degranulation of primary human mast cells in vitro was 56 nM.
Substance Class Chemical
Created
by admin
on Sat Jun 26 12:42:18 UTC 2021
Edited
by admin
on Sat Jun 26 12:42:18 UTC 2021
Record UNII
SQ8A3S5101
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
FOSTAMATINIB
INN   MI   USAN   WHO-DD  
INN   USAN  
Official Name English
2H-PYRIDO(3,2-B)-1,4-OXAZIN-3(4H)-ONE, 6-((5-FLUORO-2-((3,4,5-TRIMETHOXYPHENYL)AMINO)-4-PYRIMIDINYL)AMINO)-2,2-DIMETHYL-4-((PHOSPHONOOXY)METHYL)-
Systematic Name English
R935788 FREE ACID
Code English
(6-((5-FLUORO-2-((3,4,5-TRIMETHOXYPHENYL)AMINO)PYRIMIDIN-4-YL)AMINO)-2,2-DIMETHYL-3-OXO-2,3-DIHYDRO-4H-PYRIDO(3,2-B)(1,4)OXAZIN-4-YL)METHYL DIHYDROGEN PHOSPHATE
Systematic Name English
R-788 FREE ACID
Code English
R788 FREE ACID
Code English
FOSTAMATINIB [WHO-DD]
Common Name English
FOSTAMATINIB [INN]
Common Name English
R-935788 FREE ACID
Code English
FOSTAMATINIB [MI]
Common Name English
FOSTAMATINIB [USAN]
Common Name English
Classification Tree Code System Code
WHO-ATC B02BX09
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
FDA ORPHAN DRUG 544516
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
NCI_THESAURUS C1967
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
Code System Code Type Description
ChEMBL
CHEMBL2103830
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
PRIMARY
WIKIPEDIA
FOSTAMATINIB
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
PRIMARY
INN
9022
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
PRIMARY
NCI_THESAURUS
C95222
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
PRIMARY
DRUG CENTRAL
5280
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
PRIMARY
MESH
C523665
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
PRIMARY
PUBCHEM
11671467
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
PRIMARY
FDA UNII
SQ8A3S5101
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
PRIMARY
DRUG BANK
DB12010
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
PRIMARY
RXCUI
2044896
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
PRIMARY
CAS
901119-35-5
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
PRIMARY
EVMPD
SUB35500
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
PRIMARY
MERCK INDEX
M5557
Created by admin on Sat Jun 26 12:42:19 UTC 2021 , Edited by admin on Sat Jun 26 12:42:19 UTC 2021
PRIMARY Merck Index
Related Record Type Details
METABOLIC ENZYME -> SUBSTRATE
SALT/SOLVATE -> PARENT
TARGET -> INHIBITOR
METABOLIC ENZYME -> INHIBITOR
SALT/SOLVATE -> PARENT
METABOLIC ENZYME -> SUBSTRATE
BINDER->LIGAND
BINDING
Related Record Type Details
METABOLITE -> PARENT
PLASMA; URINE
METABOLITE ACTIVE -> PRODRUG
MAJOR
METABOLITE -> PARENT
FECAL
METABOLITE -> PARENT
METABOLITE -> PARENT
PLASMA
METABOLITE -> PARENT
PLASMA
Name Property Type Amount Referenced Substance Defining Parameters References
Volume of Distribution PHARMACOKINETIC
Biological Half-life PHARMACOKINETIC
Tmax PHARMACOKINETIC DOSE