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=C(F)C=CC(F)=C5
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: CHEMBL3559684 |
|||
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1Nausea (>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%) |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
Other AEs: Fatigue, Pyrexia... Other AEs: Fatigue (all grades, 37%) Sources: Page: Table 2Pyrexia (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: Page: Table 3 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 3 |
Other AEs: ALT increased, AST increased... Other AEs: ALT increased (all grades, 45%) Sources: Page: Table 3AST 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%) |
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 n = 7 Health Status: unhealthy Condition: solid tumours Age Group: adult Sex: unknown Population Size: 7 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 n = 6 Health Status: unhealthy Condition: solid tumours Age Group: adult Sex: unknown Population Size: 6 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: Page: 91 |
unhealthy, adult n = 6 Health Status: unhealthy Condition: solid tumor Age Group: adult Sex: unknown Population Size: 6 Sources: Page: 91 |
|
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 n = 6 Health Status: unhealthy Condition: solid tumours Age Group: adult Sex: unknown Population Size: 6 Sources: |
DLT: Dizziness... |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: 6.1 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: 6.1 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 2 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 2 |
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: Page: Table 3 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 3 |
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: Page: Table 3 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 3 |
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: Page: Table 3 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 3 |
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: Page: Table 3 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 3 |
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: Page: Table 3 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 3 |
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: Page: Table 3 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 3 |
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: Page: Table 3 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 3 |
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: Page: Table 3 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 3 |
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: Page: Table 3 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 3 |
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: Page: Table 3 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 3 |
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: Page: Table 3 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 3 |
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: Page: Table 3 |
unhealthy, 28 - 82 years n = 176 Health Status: unhealthy Condition: solid tumor Age Group: 28 - 82 years Sex: M+F Population Size: 176 Sources: Page: Table 3 |
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 n = 7 Health Status: unhealthy Condition: solid tumours Age Group: adult Sex: unknown Population Size: 7 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 n = 7 Health Status: unhealthy Condition: solid tumours Age Group: adult Sex: unknown Population Size: 7 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 n = 6 Health Status: unhealthy Condition: solid tumours Age Group: adult Sex: unknown Population Size: 6 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 n = 6 Health Status: unhealthy Condition: solid tumours Age Group: adult Sex: unknown Population Size: 6 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 |
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
by
admin
on
Edited
Sat Dec 16 09:51:56 GMT 2023
by
admin
on
Sat Dec 16 09:51:56 GMT 2023
|
Record UNII |
PF9462I9HX
|
Record Status |
Validated (UNII)
|
Record Version |
|
-
Download
Name | Type | Language | ||
---|---|---|---|---|
|
Official Name | English | ||
|
Code | English | ||
|
Code | English | ||
|
Code | English | ||
|
Common Name | English | ||
|
Systematic Name | English | ||
|
Common Name | English | ||
|
Common Name | English | ||
|
Systematic Name | English | ||
|
Common Name | English | ||
|
Code | English |
Classification Tree | Code System | Code | ||
---|---|---|---|---|
|
NCI_THESAURUS |
C129825
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
||
|
FDA ORPHAN DRUG |
578317
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
||
|
NCI_THESAURUS |
C1967
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
||
|
EU-Orphan Drug |
EU/3/18/2098
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
Code System | Code | Type | Description | ||
---|---|---|---|---|---|
|
DB14723
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
PRIMARY | |||
|
1223403-58-4
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
PRIMARY | |||
|
LOXO-101
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
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). | ||
|
5305
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
PRIMARY | |||
|
DTXSID101020707
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
PRIMARY | |||
|
C115977
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
PRIMARY | |||
|
PF9462I9HX
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
PRIMARY | |||
|
CHEMBL3545075
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
PRIMARY | |||
|
m12207
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
PRIMARY | |||
|
46188928
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
PRIMARY | |||
|
100000174559
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
PRIMARY | |||
|
2105628
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
PRIMARY | |||
|
PF9462I9HX
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
PRIMARY | |||
|
DE-156
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
PRIMARY | |||
|
ARRY 470
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
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. | ||
|
10360
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
PRIMARY | |||
|
Larotrectinib
Created by
admin on Sat Dec 16 09:51:57 GMT 2023 , Edited by admin on Sat Dec 16 09:51:57 GMT 2023
|
PRIMARY |
Related Record | Type | Details | ||
---|---|---|---|---|
|
METABOLIC ENZYME -> INDUCER |
|
||
|
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
|
||
|
SALT/SOLVATE -> PARENT |
|
||
|
TRANSPORTER -> SUBSTRATE |
In overexpressing BCRP and P-gp cell line, the estimate Km for both transporters is >300 μM.
|
||
|
TRANSPORTER -> SUBSTRATE |
In overexpressing BCRP and P-gp cell line, the estimate Km for both transporters is >300 μM. 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.
|
||
|
TARGET -> INHIBITOR |
Active against NTRK gene fusions. Competitive to ATP binding site.
COMPETITIVE INHIBITOR
IC50
|
||
|
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
|
||
|
METABOLIC ENZYME -> SUBSTRATE |
Drug interactions with Cyp3A4 inhibitors. Up to a 4.3 fold increase.
MAJOR
|
||
|
SALT/SOLVATE -> PARENT |
|
||
|
TARGET -> INHIBITOR |
IC50
|
||
|
BINDER->LIGAND |
|
||
|
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.
|
||
|
TARGET -> INHIBITOR |
IC50
|
Related Record | Type | Details | ||
---|---|---|---|---|
|
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.
|
Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
---|---|---|---|---|---|---|
Biological Half-life | PHARMACOKINETIC |
|
ORAL |
|
||
Volume of Distribution | PHARMACOKINETIC |
|
DOSE |
|
||
Tmax | PHARMACOKINETIC |
|
BID |
|
||