Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C21H22F2N6O2 |
Molecular Weight | 428.4352 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
O[C@H]1CCN(C1)C(=O)NC2=C3N=C(C=CN3N=C2)N4CCC[C@@H]4C5=CC(F)=CC=C5F
InChI
InChIKey=NYNZQNWKBKUAII-KBXCAEBGSA-N
InChI=1S/C21H22F2N6O2/c22-13-3-4-16(23)15(10-13)18-2-1-7-28(18)19-6-9-29-20(26-19)17(11-24-29)25-21(31)27-8-5-14(30)12-27/h3-4,6,9-11,14,18,30H,1-2,5,7-8,12H2,(H,25,31)/t14-,18+/m0/s1
Molecular Formula | C21H22F2N6O2 |
Molecular Weight | 428.4352 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
Larotrectinib (previously known as ARRY-470 and LOXO-101) is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs). Larotrectinib is in phase II clinical trials for the treatment patients with solid tumors, non-Hodgkin lymphoma and for the pediatric patients with advanced solid or primary CNS tumors.
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/21138586
Curator's Comment: Known to be CNS non-penetrant in mouse. Human data not available
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2815 |
20.0 nM [IC50] | ||
Target ID: CHEMBL4898 |
20.0 nM [IC50] | ||
Target ID: CHEMBL5608 |
20.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | VITRAKVI Approved UseVitrakvi is specifically indicated for the treatment of adult and pediatric patients with solid tumors that: • have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, • are metastatic or where surgical resection is likely to result in severe morbidity, and • have no satisfactory alternative treatments or that have progressed following treatment. Launch Date2018 |
|||
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
788 ng/mL |
100 mg 2 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
LAROTRECTINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
4351 ng × h/mL |
100 mg 2 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
LAROTRECTINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2.9 h |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
LAROTRECTINIB plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Other AEs: Fatigue, Pyrexia... Other AEs: Fatigue (all grades, 37%) Sources: Pyrexia (all grades, 18%) Edema peripheral (all grades, 15%) Nausea (all grades, 29%) Vomiting (all grades, 26%) Constipation (all grades, 23%) Diarrhea (all grades, 22%) Abdominal pain (all grades, 13%) Dizziness (all grades, 28%) Headache (all grades, 14%) Cough (all grades, 26%) Dyspnea (all grades, 18%) Nasal congestion (all grades, 10%) Fatigue (grade 3-4, 3%) Pyrexia (grade 3-4, 1%) Nausea (grade 3-4, 1%) Vomiting (grade 3-4, 1%) Constipation (grade 3-4, 1%) Diarrhea (grade 3-4, 2%) Abdominal pain (grade 3-4, 2%) Dizziness (grade 3-4, 1%) Dyspnea (grade 3-4, 2%) Weight increased (all grades, 15%) Arthralgia (all grades, 14%) Myalgia (all grades, 14%) Muscular weakness (all grades, 13%) Back pain (all grades, 12%) Pain in extremity (all grades, 12%) Decreased appetite (all grades, 13%) Decreased appetite (all grades, 11%) Weight increased (grade 3-4, 4%) Arthralgia (grade 3-4, 1%) Myalgia (grade 3-4, 1%) Back pain (grade 3-4, 1%) Pain in extremity (grade 3-4, 1%) Decreased appetite (grade 3-4, 2%) Decreased appetite (grade 3-4, 2%) |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Other AEs: ALT increased, AST increased... Other AEs: ALT increased (all grades, 45%) Sources: AST increased (all grades, 45%) Hypoalbuminemia (all grades, 35%) Alkaline phosphatase increased (all grades, 30%) Anemia (all grades, 42%) Neutropenia (all grades, 23%) ALT increased (grade 3-4, 3%) AST increased (grade 3-4, 3%) Hypoalbuminemia (grade 3-4, 2%) Alkaline phosphatase increased (grade 3-4, 3%) Anemia (grade 3-4, 10%) Neutropenia (grade 3-4, 7%) |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Disc. AE: Brain edema, Intestinal perforation... Other AEs: Fatigue, Nausea... AEs leading to discontinuation/dose reduction: Brain edema (1 - 2) Other AEs:Intestinal perforation (1 - 2) Pericardial effusion (1 - 2) Pleural effusion (1 - 2) Small intestinal obstruction (1 - 2) Dehydration (1 - 2) Fatigue (1 - 2) ALT increased (1 - 2) AST increased (1 - 2) Enterocutaneous fistula (1 - 2) Amylase increased (1 - 2) Lipase increased (1 - 2) Muscular weakness (1 - 2) Abdominal pain (1 - 2) Asthenia (1 - 2) Decreased appetite (1 - 2) Dyspnea (1 - 2) Hyponatremia (1 - 2) Jaundice (1 - 2) Syncope (1 - 2) Vomiting (1 - 2) Nausea (1 - 2) Acute myeloid leukemia (1 - 2) Fatigue (>20) Sources: Nausea (>20) Dizziness (>20) Vomiting (>20) Anemia (>20) AST increased (>20) Cough (>20) ALT increased (>20) Constipation (>20) Diarrhea (>20) ALT increased (6%) AST increased (6%) Dizziness (3%) |
150 mg 2 times / day steady, oral Higher than recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sex: unknown Sources: |
DLT: Alanine aminotransferase increased, Aspartate aminotransferase increased... Dose limiting toxicities: Alanine aminotransferase increased (1 patient) Sources: Aspartate aminotransferase increased (1 patient) |
200 mg 2 times / day steady, oral Highest studied dose Dose: 200 mg, 2 times / day Route: oral Route: steady Dose: 200 mg, 2 times / day Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sex: unknown Sources: |
DLT: Dizziness... |
200 mg 2 times / day steady, oral Highest studied dose Dose: 200 mg, 2 times / day Route: oral Route: steady Dose: 200 mg, 2 times / day Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sex: unknown Sources: |
|
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sex: unknown Sources: |
DLT: Dizziness... |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Nasal congestion | all grades, 10% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Decreased appetite | all grades, 11% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Back pain | all grades, 12% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Pain in extremity | all grades, 12% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Abdominal pain | all grades, 13% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Decreased appetite | all grades, 13% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Muscular weakness | all grades, 13% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Arthralgia | all grades, 14% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Headache | all grades, 14% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Myalgia | all grades, 14% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Edema peripheral | all grades, 15% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Weight increased | all grades, 15% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Dyspnea | all grades, 18% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Pyrexia | all grades, 18% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Diarrhea | all grades, 22% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Constipation | all grades, 23% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Cough | all grades, 26% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Vomiting | all grades, 26% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Dizziness | all grades, 28% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Nausea | all grades, 29% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Fatigue | all grades, 37% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Arthralgia | grade 3-4, 1% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Back pain | grade 3-4, 1% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Constipation | grade 3-4, 1% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Dizziness | grade 3-4, 1% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Myalgia | grade 3-4, 1% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Nausea | grade 3-4, 1% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Pain in extremity | grade 3-4, 1% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Pyrexia | grade 3-4, 1% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Vomiting | grade 3-4, 1% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Abdominal pain | grade 3-4, 2% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Decreased appetite | grade 3-4, 2% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Decreased appetite | grade 3-4, 2% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Diarrhea | grade 3-4, 2% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Dyspnea | grade 3-4, 2% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Fatigue | grade 3-4, 3% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Weight increased | grade 3-4, 4% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Neutropenia | all grades, 23% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Alkaline phosphatase increased | all grades, 30% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Hypoalbuminemia | all grades, 35% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Anemia | all grades, 42% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
ALT increased | all grades, 45% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
AST increased | all grades, 45% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Anemia | grade 3-4, 10% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Hypoalbuminemia | grade 3-4, 2% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
ALT increased | grade 3-4, 3% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
AST increased | grade 3-4, 3% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Alkaline phosphatase increased | grade 3-4, 3% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Neutropenia | grade 3-4, 7% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
ALT increased | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
AST increased | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Abdominal pain | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Acute myeloid leukemia | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Amylase increased | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Asthenia | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Brain edema | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Decreased appetite | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Dehydration | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Dyspnea | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Enterocutaneous fistula | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Fatigue | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Hyponatremia | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Intestinal perforation | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Jaundice | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Lipase increased | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Muscular weakness | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Nausea | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Pericardial effusion | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Pleural effusion | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Small intestinal obstruction | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Syncope | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Vomiting | 1 - 2 Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Dizziness | 3% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
ALT increased | 6% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
AST increased | 6% | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
ALT increased | >20 | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
AST increased | >20 | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Anemia | >20 | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Constipation | >20 | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Cough | >20 | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Diarrhea | >20 | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Dizziness | >20 | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Fatigue | >20 | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Nausea | >20 | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Vomiting | >20 | 100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, 28 - 82 years Health Status: unhealthy Age Group: 28 - 82 years Sex: M+F Sources: |
Alanine aminotransferase increased | 1 patient DLT |
150 mg 2 times / day steady, oral Higher than recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sex: unknown Sources: |
Aspartate aminotransferase increased | 1 patient DLT |
150 mg 2 times / day steady, oral Higher than recommended Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sex: unknown Sources: |
Dizziness | 1 patient DLT |
200 mg 2 times / day steady, oral Highest studied dose Dose: 200 mg, 2 times / day Route: oral Route: steady Dose: 200 mg, 2 times / day Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sex: unknown Sources: |
Dizziness | 1 patient DLT |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sex: unknown Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
yes | ||||
yes | yes (co-administration study) Comment: larotrectinib increased midazolam both AUC and Cmax by 1.7-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210861Orig1s000_211710Orig1s000MultidisciplineR.pdf Page: 94.0 |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
yes [Km >300 uM] | ||||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210861Orig1s000_211710Orig1s000MultidisciplineR.pdf Page: 93, 94, 106 |
yes [Km >300 uM] | yes (co-administration study) Comment: rifampin increased larotrectinib AUC by 1.7-fold and Cmax by 1.8-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210861Orig1s000_211710Orig1s000MultidisciplineR.pdf Page: 93, 94, 106 |
||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210861Orig1s000_211710Orig1s000MultidisciplineR.pdf#page=95 Page: 95, 104, 105 |
yes | yes (co-administration study) Comment: coadministration with midazolam increased midazolam AUC and Cmax by 1.7-fold; itraconazole increased larotrectinib AUC by 4.3-fold and Cmax by 2.8-fold; rifampin decreased larotrectinib AUC by 81% and Cmax by 71% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210861Orig1s000_211710Orig1s000MultidisciplineR.pdf#page=95 Page: 95, 104, 105 |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210861Orig1s000_211710Orig1s000MultidisciplineR.pdf Page: 44, 51, 182 |
PubMed
Title | Date | PubMed |
---|---|---|
An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. | 2015 Oct |
|
Targeting NTRK fusion in non-small cell lung cancer: rationale and clinical evidence. | 2017 Jun |
|
Rapid Response to Larotrectinib (LOXO-101) in an Adult Chemotherapy-Naive Patients With Advanced Triple-Negative Secretory Breast Cancer Expressing ETV6-NTRK3 Fusion. | 2018 Jun |
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT02576431
Oral capsule of LOXO-101 (ARRY-470 (FREE BASE)) - 100mg BID
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24162815
ARRY-470 is a selective kinase inhibitor with nanomolar activity against TRKA/B/C but no other significant kinase inhibition below 1000nM. Treatment of cells expressing MPRIP- or CD74-NTRK1 with ARRY-470, CEP-701 and, to a lesser extent, crizotinib, inhibited autophosphorylation of RIP-TRKA and CD74-TRKA. It induces cell-cycle arrest in G1 and apoptosis of KM12 cells.
Substance Class |
Chemical
Created
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on
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Mon Mar 31 22:52:53 GMT 2025
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Record UNII |
PF9462I9HX
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Validated (UNII)
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Classification Tree | Code System | Code | ||
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NCI_THESAURUS |
C129825
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FDA ORPHAN DRUG |
578317
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NCI_THESAURUS |
C1967
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EU-Orphan Drug |
EU/3/18/2098
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Code System | Code | Type | Description | ||
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DB14723
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1223403-58-4
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LOXO-101
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PRIMARY | MedKoo CAT NO: 206207CAS NO: 1223403-58-4Description: LOXO-101, also known as ARRY-470, is an orally bioavailable, potent, ATP-competitive inhibitor of TRKA, TRKB, and TRKC. LOXO-101 has IC50 values in the low nanomolar range for inhibition of all three TRK family members in binding and cellular assays, with 100x selectivity over other kinases, and has shown acceptable pharmaceutical properties and safety in nonclinical models. The TRK family of neurotrophin receptors, TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3 genes, respectively) and their neurotrophin ligands regulate growth, differentiation and survival of neurons. (Last updated: 6/9/2016). | ||
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DTXSID101020707
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C115977
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m12207
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DE-156
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ARRY 470
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PRIMARY | Biological Activity: LOXO-101 is an orally bioavailable, potent, ATP-competitive inhibitor of TRKA, TRKB, and TRKC. LOXO-101 has IC50 values in the low nanomolar range for inhibition of all three TRK family members in binding and cellular assays, with 100x selectivity over other kinases, and has shown acceptable pharmaceutical properties and safety in nonclinical models. The TRK family of neurotrophin receptors, TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3 genes, respectively) and their neurotrophin ligands regulate growth, differentiation and survival of neurons. Translocations involving the TRK kinase domain, mutations involving the TRK ligand-binding site, amplifications of NTRK, TRK splice variants, and autocrine/paracrine signaling are described in diverse tumor types, and may contribute to tumorigenesis. LOXO-101 is currently being developed by Loxo Oncology, Inc. | ||
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10360
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Larotrectinib
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PRIMARY |
Related Record | Type | Details | ||
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METABOLIC ENZYME -> INDUCER |
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EXCRETED UNCHANGED |
mediated primarily by oxidative N-dealkylation with the subsequent
cleavage of the 3-hydroxypyrrolidine carboxamide moiety and
formation of the secondary glucuronide M14, the most abundant
circulating and excreted metabolite.
FECAL
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SALT/SOLVATE -> PARENT |
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TRANSPORTER -> SUBSTRATE |
In overexpressing BCRP and P-gp cell line, the estimate Km for both transporters is >300 ?M.
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TRANSPORTER -> SUBSTRATE |
In overexpressing BCRP and P-gp cell line, the estimate Km for both transporters is >300 ?M. Coadministration of larotrectinib with a single dose of a P-gp inhibitor (rifampin), increased the AUCinf of larotrectinib by 1.7-fold and the Cmax by 1.8-fold as compared to larotrectinib administered alone.
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EXCRETED UNCHANGED |
Following oral administration of a single [14C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, 58% (5% unchanged) of the administered radioactivity was recovered in feces and 39% (20% unchanged) was recovered in urine
URINE
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METABOLIC ENZYME -> SUBSTRATE |
Drug interactions with Cyp3A4 inhibitors. Up to a 4.3 fold increase.
MAJOR
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TARGET -> INHIBITOR | |||
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SALT/SOLVATE -> PARENT |
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TARGET -> INHIBITOR |
IC50
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BINDER->LIGAND |
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METABOLIC ENZYME -> INHIBITOR |
Coadministration of multiple doses of larotrectinib with a sensitive CYP3A4 substrate (midazolam) increased the AUCinf and Cmax of midazolam by 1.7-fold as compared to midazolam administered alone.
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TARGET -> INHIBITOR |
IC50
|
Related Record | Type | Details | ||
---|---|---|---|---|
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ACTIVE MOIETY |
LOXO-101 has IC50 values in the low nanomolar range for inhibition of all three TRK family members in binding and cellular assays, with 100x selectivity over other
kinases, and has shown acceptable pharmaceutical properties and safety in preclinical models. LOXO-101 is an orally bioavailable, potent, ATP-competitive
inhibitor of TRKA, TRKB, and TRKC. LOXO-101 has IC50 values in the low nanomolar range for inhibition of all three TRK family members
in binding and cellular assays, with 100x selectivity over other
kinases, and has shown acceptable pharmaceutical properties and safety in nonclinical models.
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Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Biological Half-life | PHARMACOKINETIC |
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ORAL |
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Volume of Distribution | PHARMACOKINETIC |
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DOSE |
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Tmax | PHARMACOKINETIC |
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BID |
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