Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | 2C31H33N5O4.2C2H6O3S.H2O |
| Molecular Weight | 1317.529 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 2 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
O.CCS(O)(=O)=O.CCS(O)(=O)=O.COC(=O)C1=CC=C2C(NC(=O)\C2=C(/NC3=CC=C(C=C3)N(C)C(=O)CN4CCN(C)CC4)C5=CC=CC=C5)=C1.COC(=O)C6=CC=C7C(NC(=O)\C7=C(/NC8=CC=C(C=C8)N(C)C(=O)CN9CCN(C)CC9)C%10=CC=CC=C%10)=C6
InChI
InChIKey=FXFVOZKAPICGNY-NKYWIEMRSA-N
InChI=1S/2C31H33N5O4.2C2H6O3S.H2O/c2*1-34-15-17-36(18-16-34)20-27(37)35(2)24-12-10-23(11-13-24)32-29(21-7-5-4-6-8-21)28-25-14-9-22(31(39)40-3)19-26(25)33-30(28)38;2*1-2-6(3,4)5;/h2*4-14,19,32H,15-18,20H2,1-3H3,(H,33,38);2*2H2,1H3,(H,3,4,5);1H2/b2*29-28-;;;
DescriptionCurator's Comment: description was created based on several sources, including http://www.ncbi.nlm.nih.gov/pubmed/?term=24782550; http://www.ncbi.nlm.nih.gov/pubmed/?term=21204634;
http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2016/6-6-2016-boehringer-ingelheim-inventiva-collaborate-develop-potential-new-treatments-idiopathic-pulmonary-fibrosis.html
Curator's Comment: description was created based on several sources, including http://www.ncbi.nlm.nih.gov/pubmed/?term=24782550; http://www.ncbi.nlm.nih.gov/pubmed/?term=21204634;
http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2016/6-6-2016-boehringer-ingelheim-inventiva-collaborate-develop-potential-new-treatments-idiopathic-pulmonary-fibrosis.html
Nintedanib is a receptor tyrosine kinase inhibitor with potential antiangiogenic and antineoplastic activities. It is the only kinase inhibitor drug approved to treat idiopathic pulmonary fibrosis. that targets multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Nintedanib inhibits the following RTKs: platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, and Fms-like tyrosine kinase-3 (FLT3). Among them, FGFR, PDGFR, and VEGFR have been implicated in IPF pathogenesis. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signaling which is crucial for the proliferation, migration, and transformation of fibroblasts representing essential mechanisms of the IPF pathology.
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: P17948|||B3FR89 Gene ID: 2321.0 Gene Symbol: FLT1 Target Organism: Homo sapiens (Human) |
34.0 nM [IC50] | ||
Target ID: P35968 Gene ID: 3791.0 Gene Symbol: KDR Target Organism: Homo sapiens (Human) |
21.0 nM [IC50] | ||
Target ID: P35916 Gene ID: 2324.0 Gene Symbol: FLT4 Target Organism: Homo sapiens (Human) |
13.0 nM [IC50] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | OFEV Approved UseIndicated for the treatment of idiopathic pulmonary fibrosis (IPF) Launch Date2014 |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
8.4 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/27093880 |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
NINTEDANIB plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
56.2 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/27093880 |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
NINTEDANIB plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
11.7 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/27093880 |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
NINTEDANIB plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
Funbound
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
2.2% |
NINTEDANIB plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Doses
| Dose | Population | Adverse events |
|---|---|---|
200 mg 1 times / day steady, oral Dose: 200 mg, 1 times / day Route: oral Route: steady Dose: 200 mg, 1 times / day Sources: |
unhealthy, 61 years n = 6 Health Status: unhealthy Age Group: 61 years Sex: M+F Population Size: 6 Sources: |
DLT: Gamma-glutamyltransferase increased... Dose limiting toxicities: Gamma-glutamyltransferase increased (grade 3, 1 patient) Sources: |
250 mg 1 times / day steady, oral Dose: 250 mg, 1 times / day Route: oral Route: steady Dose: 250 mg, 1 times / day Sources: |
unhealthy, 61 years n = 4 Health Status: unhealthy Age Group: 61 years Sex: M+F Population Size: 4 Sources: |
DLT: Gamma-glutamyltransferase increased... Dose limiting toxicities: Gamma-glutamyltransferase increased (grade 3, 1 patient) Sources: |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: |
Disc. AE: Diarrhea, Nausea... AEs leading to discontinuation/dose reduction: Diarrhea (5%) Sources: Nausea (2%) Decreased appetite (2%) |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 15 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 15 |
Disc. AE: Weight decreased, Alanine aminotransferase increased... AEs leading to discontinuation/dose reduction: Weight decreased (1.1%) Sources: Page: p. 15Alanine aminotransferase increased (0.6%) |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 87 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 87 |
Disc. AE: Vomiting, Abdominal pain... AEs leading to discontinuation/dose reduction: Vomiting (1%) Sources: Page: p. 87Abdominal pain (1%) Asthenia (0.7%) Hepatic enzyme increased (0.6%) Aspartate aminotransferase increased (0.4%) Blood bilirubin increased (0.4%) |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 88 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 88 |
Disc. AE: Diarrhea, Nausea... AEs leading to discontinuation/dose reduction: Diarrhea (10.9%) Sources: Page: p. 88Nausea (2.1%) Decreased appetite (0.8%) Weight decreased (0.6%) Abdominal pain (0.8%) Abdominal pain upper (0.8%) Transaminases increased (0.4%) Hepatic function abnormal (0.7%) |
250 mg 2 times / day steady, oral MTD Dose: 250 mg, 2 times / day Route: oral Route: steady Dose: 250 mg, 2 times / day Sources: |
unhealthy, adult n = 11 Health Status: unhealthy Condition: advanced solid tumors Age Group: adult Population Size: 11 Sources: |
DLT: Elevated liver enzymes... Dose limiting toxicities: Elevated liver enzymes (grade 3, 2 patients) Sources: |
600 mg 1 times / day multiple, oral Overdose Dose: 600 mg, 1 times / day Route: oral Route: multiple Dose: 600 mg, 1 times / day Sources: |
unhealthy, adult n = 1 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: adult Population Size: 1 Sources: |
Other AEs: Nasopharyngitis... Other AEs: Nasopharyngitis Sources: |
600 mg 2 times / day multiple, oral Overdose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: |
unhealthy, adult n = 2 Health Status: unhealthy Condition: cancer Age Group: adult Population Size: 2 Sources: |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Gamma-glutamyltransferase increased | grade 3, 1 patient DLT |
200 mg 1 times / day steady, oral Dose: 200 mg, 1 times / day Route: oral Route: steady Dose: 200 mg, 1 times / day Sources: |
unhealthy, 61 years n = 6 Health Status: unhealthy Age Group: 61 years Sex: M+F Population Size: 6 Sources: |
| Gamma-glutamyltransferase increased | grade 3, 1 patient DLT |
250 mg 1 times / day steady, oral Dose: 250 mg, 1 times / day Route: oral Route: steady Dose: 250 mg, 1 times / day Sources: |
unhealthy, 61 years n = 4 Health Status: unhealthy Age Group: 61 years Sex: M+F Population Size: 4 Sources: |
| Decreased appetite | 2% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: |
| Nausea | 2% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: |
| Diarrhea | 5% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: |
| Alanine aminotransferase increased | 0.6% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 15 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 15 |
| Weight decreased | 1.1% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 15 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 15 |
| Aspartate aminotransferase increased | 0.4% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 87 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 87 |
| Blood bilirubin increased | 0.4% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 87 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 87 |
| Hepatic enzyme increased | 0.6% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 87 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 87 |
| Asthenia | 0.7% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 87 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 87 |
| Abdominal pain | 1% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 87 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 87 |
| Vomiting | 1% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 87 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 87 |
| Transaminases increased | 0.4% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 88 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 88 |
| Weight decreased | 0.6% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 88 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 88 |
| Hepatic function abnormal | 0.7% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 88 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 88 |
| Abdominal pain upper | 0.8% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 88 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 88 |
| Abdominal pain | 0.8% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 88 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 88 |
| Decreased appetite | 0.8% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 88 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 88 |
| Diarrhea | 10.9% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 88 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 88 |
| Nausea | 2.1% Disc. AE |
150 mg 2 times / day steady, oral Recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: Page: p. 88 |
unhealthy, 67 years (range: 42 - 89 years) n = 723 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: 67 years (range: 42 - 89 years) Sex: M+F Population Size: 723 Sources: Page: p. 88 |
| Elevated liver enzymes | grade 3, 2 patients DLT |
250 mg 2 times / day steady, oral MTD Dose: 250 mg, 2 times / day Route: oral Route: steady Dose: 250 mg, 2 times / day Sources: |
unhealthy, adult n = 11 Health Status: unhealthy Condition: advanced solid tumors Age Group: adult Population Size: 11 Sources: |
| Nasopharyngitis | 600 mg 1 times / day multiple, oral Overdose Dose: 600 mg, 1 times / day Route: oral Route: multiple Dose: 600 mg, 1 times / day Sources: |
unhealthy, adult n = 1 Health Status: unhealthy Condition: idiopathic pulmonary fibrosis Age Group: adult Population Size: 1 Sources: |
Overview
| CYP3A4 | CYP2C9 | CYP2D6 | hERG |
|---|---|---|---|
OverviewOther
| Other Inhibitor | Other Substrate | Other Inducer |
|---|---|---|
Drug as perpetrator
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
| no [IC50 16 uM] | ||||
| no [IC50 24.5 uM] | ||||
| no [IC50 24.5 uM] | ||||
| no [IC50 70.1 uM] | ||||
| no [IC50 77.6 uM] | ||||
| no [IC50 85.5 uM] | ||||
| no [IC50 >200 uM] | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| weak | ||||
| weak | ||||
| weak | ||||
| weak | ||||
| yes [IC50 0.88 uM] |
Drug as victim
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
| major | ||||
| minor | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | ||||
| yes | yes (co-administration study) Comment: Coadministration with the P-gp and CYP3A4 inhibitor ketoconazole increased exposure of nintedanib by 1.61-fold based on AUC and 1.83-fold based on Cmax. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205832Orig1s000ClinPharmR.pdf#page=9 Page: 9.0 |
Tox targets
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
PubMed
| Title | Date | PubMed |
|---|---|---|
| BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. | 2008 Jun 15 |
|
| Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers. | 2011 Apr |
|
| A new hope for idiopathic pulmonary fibrosis. | 2014 May 29 |
|
| Nintedanib: a novel therapeutic approach for idiopathic pulmonary fibrosis. | 2014 Sep |
|
| Nintedanib: A Review of Its Use in Patients with Idiopathic Pulmonary Fibrosis. | 2015 Jul |
|
| Nintedanib in the treatment of idiopathic pulmonary fibrosis. | 2015 Jun |
Sample Use Guides
150 mg twice daily approximately 12 hours apart
taken with food. Recommended dosage in patients with mild hepatic impairment: 100 mg twice daily approximately 12 hours apart taken with food. Consider temporary dose reduction to 100 mg, treatment interruption, or discontinuation for management of adverse reactions. Prior to treatment, conduct liver function tests and a pregnancy test
Route of Administration:
Oral
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959762-24-4
Created by
admin on Fri Dec 15 15:30:16 GMT 2023 , Edited by admin on Fri Dec 15 15:30:16 GMT 2023
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PRIMARY | |||
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23O68KB9KV
Created by
admin on Fri Dec 15 15:30:16 GMT 2023 , Edited by admin on Fri Dec 15 15:30:16 GMT 2023
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PRIMARY |
ACTIVE MOIETY
SUBSTANCE RECORD
