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Details

Stereochemistry ACHIRAL
Molecular Formula C31H34F2N6O2
Molecular Weight 560.6386
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ENTRECTINIB

SMILES

CN1CCN(CC1)c2ccc(c(c2)NC3CCOCC3)C(=O)N=c4c5cc(ccc5[nH][nH]4)Cc6cc(cc(c6)F)F

InChI

InChIKey=HAYYBYPASCDWEQ-UHFFFAOYSA-N
InChI=1S/C31H34F2N6O2/c1-38-8-10-39(11-9-38)25-3-4-26(29(19-25)34-24-6-12-41-13-7-24)31(40)35-30-27-17-20(2-5-28(27)36-37-30)14-21-15-22(32)18-23(33)16-21/h2-5,15-19,24,34H,6-14H2,1H3,(H2,35,36,37,40)

HIDE SMILES / InChI

Description
Curator's Comment:: Description was created based on several sources, including http://ignyta.com/providers/rx-precision-medicine-pipeline/entrectinib/ http://www.medscape.com/viewarticle/862131

Entrectinib (previously known as RXDX-101, NMS-E628) is an investigational drug, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Entrectinib (RXDX-101) is a selective inhibitor for all three Trk receptor tyrosine kinases encoded by the three NTRK genes, as well as the ROS1 and ALKreceptor tyrosine kinases.This investigational drug is active at low nanomolar concentrations, allowing for once-daily oral administration to patients whose tumors have been shown to have gene rearrangements in NTRK, ROS1, or ALK. Nerviano Medical Sciences, the original sponsor for entrectinib (formerly referred to as NMS-1191372), initiated the first-in-human Phase 1 study ALKA-372-001 in Italy in October 2012. The study is currently ongoing in Italy. Entrectinib is currently being tested in a global phase 2 basket clinical trial called STARTRK-2. In the U.S., entrectinib has orphan drug designation and rare pediatric disease designation for the treatment of neuroblastoma and orphan drug designation for treatment of TrkA-, TrkB-, TrkC-, ROS1- and ALK-positive non-small cell lung cancer (NSCLC) and metastatic colorectal cancer (mCRC).

CNS Activity

Curator's Comment:: efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
1.7 nM [IC50]
0.1 nM [IC50]
0.1 nM [IC50]
0.2 nM [IC50]
1.6 nM [IC50]
Conditions
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
2250 nM
600 mg single, oral
dose: 600 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
ENTRECTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
31800 nM × h
600 mg single, oral
dose: 600 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
ENTRECTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
20 h
600 mg single, oral
dose: 600 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
ENTRECTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
1%
600 mg single, oral
dose: 600 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
ENTRECTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
550 mg/m2 1 times / day steady, oral
Dose: 550 mg/m2, 1 times / day
Route: oral
Route: steady
Dose: 550 mg/m2, 1 times / day
Sources:
unhealthy, 2-21 years
n = 6
Health Status: unhealthy
Age Group: 2-21 years
Population Size: 6
Sources:
DLT: Creatinine increased...
Dose limiting toxicities:
Creatinine increased (grade 2, 1 patient)
Sources:
750 mg/m2 1 times / day steady, oral
Dose: 750 mg/m2, 1 times / day
Route: oral
Route: steady
Dose: 750 mg/m2, 1 times / day
Sources:
unhealthy, 2-21 years
n = 3
Health Status: unhealthy
Age Group: 2-21 years
Population Size: 3
Sources:
DLT: Dysgeusia, Fatigue...
Dose limiting toxicities:
Dysgeusia (grade 2, 1 patient)
Fatigue (grade 2, 1 patient)
Pulmonary edema (grade 3, 1 patient)
Sources:
800 mg 1 times / day steady, oral
Dose: 800 mg, 1 times / day
Route: oral
Route: steady
Dose: 800 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 18–80 years)
n = 65
Health Status: unhealthy
Age Group: 55 years (range: 18–80 years)
Sex: M+F
Population Size: 65
Sources:
DLT: Cognitive disturbance, Fatigue...
Other AEs: Eosinophilic myocarditis...
Dose limiting toxicities:
Cognitive disturbance (grade 3, 1 patient)
Fatigue (grade 3, 1 patient)
Other AEs:
Eosinophilic myocarditis (grade 4, 1 patient)
Sources:
600 mg 1 times / day steady, oral
Recommended|MTD
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Disc. AE: Pneumonia, Cardio-respiratory arrest...
AEs leading to
discontinuation/dose reduction:
Pneumonia (0.3%)
Cardio-respiratory arrest (0.6%)
Dyspnea (0.6%)
Fatigue (0.6%)
Sources:
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources:
Disc. AE: Blood creatinine increased, Fatigue...
AEs leading to
discontinuation/dose reduction:
Blood creatinine increased (4%)
Fatigue (3.7%)
Anemia (3.1%)
Diarrhea (2.8%)
Pyrexia (2.8%)
Dizziness (2.5%)
Dyspnea (2.3%)
Nausea (2.3%)
Pneumonia (2.3%)
Cognitive disorder (2%)
Neutropenia (2%)
Weight increased (1.4%)
Sources:
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources: Page: p. 149
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources: Page: p. 149
Disc. AE: Pulmonary edema, Pulmonary embolism...
AEs leading to
discontinuation/dose reduction:
Pulmonary edema (0.3%)
Pulmonary embolism (0.3%)
Myocarditis (0.3%)
Cardiogenic shock (0.3%)
Pericardial effusion (0.3%)
Malaise (0.3%)
Peripheral edema (0.3%)
Sepsis (0.3%)
Sources: Page: p. 149
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources: Page: p. 150
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources: Page: p. 150
Disc. AE: Decreased appetite, Hypotension...
AEs leading to
discontinuation/dose reduction:
Decreased appetite (1.1%)
Hypotension (1.1%)
Hypoxia (0.8%)
Sources: Page: p. 150
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources: Page: p. 151
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources: Page: p. 151
Disc. AE: Arthralgia...
AEs leading to
discontinuation/dose reduction:
Arthralgia (1%)
Sources: Page: p. 151
AEs

AEs

AESignificanceDosePopulation
Creatinine increased grade 2, 1 patient
DLT
550 mg/m2 1 times / day steady, oral
Dose: 550 mg/m2, 1 times / day
Route: oral
Route: steady
Dose: 550 mg/m2, 1 times / day
Sources:
unhealthy, 2-21 years
n = 6
Health Status: unhealthy
Age Group: 2-21 years
Population Size: 6
Sources:
Dysgeusia grade 2, 1 patient
DLT
750 mg/m2 1 times / day steady, oral
Dose: 750 mg/m2, 1 times / day
Route: oral
Route: steady
Dose: 750 mg/m2, 1 times / day
Sources:
unhealthy, 2-21 years
n = 3
Health Status: unhealthy
Age Group: 2-21 years
Population Size: 3
Sources:
Fatigue grade 2, 1 patient
DLT
750 mg/m2 1 times / day steady, oral
Dose: 750 mg/m2, 1 times / day
Route: oral
Route: steady
Dose: 750 mg/m2, 1 times / day
Sources:
unhealthy, 2-21 years
n = 3
Health Status: unhealthy
Age Group: 2-21 years
Population Size: 3
Sources:
Pulmonary edema grade 3, 1 patient
DLT
750 mg/m2 1 times / day steady, oral
Dose: 750 mg/m2, 1 times / day
Route: oral
Route: steady
Dose: 750 mg/m2, 1 times / day
Sources:
unhealthy, 2-21 years
n = 3
Health Status: unhealthy
Age Group: 2-21 years
Population Size: 3
Sources:
Cognitive disturbance grade 3, 1 patient
DLT, Disc. AE
800 mg 1 times / day steady, oral
Dose: 800 mg, 1 times / day
Route: oral
Route: steady
Dose: 800 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 18–80 years)
n = 65
Health Status: unhealthy
Age Group: 55 years (range: 18–80 years)
Sex: M+F
Population Size: 65
Sources:
Fatigue grade 3, 1 patient
DLT, Disc. AE
800 mg 1 times / day steady, oral
Dose: 800 mg, 1 times / day
Route: oral
Route: steady
Dose: 800 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 18–80 years)
n = 65
Health Status: unhealthy
Age Group: 55 years (range: 18–80 years)
Sex: M+F
Population Size: 65
Sources:
Eosinophilic myocarditis grade 4, 1 patient
800 mg 1 times / day steady, oral
Dose: 800 mg, 1 times / day
Route: oral
Route: steady
Dose: 800 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 18–80 years)
n = 65
Health Status: unhealthy
Age Group: 55 years (range: 18–80 years)
Sex: M+F
Population Size: 65
Sources:
Pneumonia 0.3%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Cardio-respiratory arrest 0.6%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Dyspnea 0.6%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Fatigue 0.6%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Weight increased 1.4%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources:
Cognitive disorder 2%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources:
Neutropenia 2%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources:
Dyspnea 2.3%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources:
Nausea 2.3%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources:
Pneumonia 2.3%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources:
Dizziness 2.5%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources:
Diarrhea 2.8%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources:
Pyrexia 2.8%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources:
Anemia 3.1%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources:
Fatigue 3.7%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources:
Blood creatinine increased 4%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources:
Cardiogenic shock 0.3%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources: Page: p. 149
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources: Page: p. 149
Malaise 0.3%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources: Page: p. 149
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources: Page: p. 149
Myocarditis 0.3%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources: Page: p. 149
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources: Page: p. 149
Pericardial effusion 0.3%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources: Page: p. 149
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources: Page: p. 149
Peripheral edema 0.3%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources: Page: p. 149
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources: Page: p. 149
Pulmonary edema 0.3%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources: Page: p. 149
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources: Page: p. 149
Pulmonary embolism 0.3%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources: Page: p. 149
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources: Page: p. 149
Sepsis 0.3%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources: Page: p. 149
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources: Page: p. 149
Hypoxia 0.8%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources: Page: p. 150
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources: Page: p. 150
Decreased appetite 1.1%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources: Page: p. 150
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources: Page: p. 150
Hypotension 1.1%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources: Page: p. 150
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources: Page: p. 150
Arthralgia 1%
Disc. AE
600 mg 1 times / day steady, oral
Recommended|MTD
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources: Page: p. 151
unhealthy, 55 years (range: 4 - 86 years)
n = 355
Health Status: unhealthy
Age Group: 55 years (range: 4 - 86 years)
Sex: M+F
Population Size: 355
Sources: Page: p. 151
Overview

Overview

Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
likely
no (co-administration study)
Comment: Clinical DDI study with midazolam showed no induction.
Page: NDA212726-115
weak
yes (co-administration study)
Comment: Coadministration of entrectinib single dose 600 mg (one hour prior to digoxin (0.5 mg) administration) increased the Cmax and AUC of P‐gp substrate digoxin by 28% and 18%, respectively. Dose adjustment for P‐gp substrate when coadministered with P‐gp inhibitor is not needed.
Page: NDA212726-115, 134
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes (co-administration study)
Comment: Coadministration of entrectinib did not increase the AUC of midazolam (sensitive CYP3A4 substrate, 2 mg SD) after a single dose 600 mg but increase the AUC of midazolam (2 mg SD) by 50% after repeat dosing at 600 mg (14 days). Cmax of midazolam were decreased by 34% after a single dose and 21% after repeat dosing (14 days) of entrectinib. No dose adjustment is needed for sensitive CYP3A substrates when coadministered with entrectinib.
Page: NDA212726-115, 132, 133
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
major
yes (co-administration study)
Comment: When a single dose of 100 mg entrectinib is coadministered with strong CYP3A inhibitor itraconazole, the GMR (90% CI) of Cmax, AUClast and AUCINF of entrectinib were 1.73 (1.37, 2.18), 5.26 (4.01, 6.91) and 6.04 (4.54, 8.04), respectively. Dose adjustment is recommended when entrectinib is coadministered with strong or moderate CYP3A4 inhibitors. Coadministration of entrectinib (600 mg SD) with multiple doses of a strong CYP3A4 inducer rifampin (600 mg QD x 14 days) decreased the Cmax and AUCINF of entrectinib by 56% and 77%, respectively. Coadministration of strong or moderate inducers of CYP3A4 with entrectinib should be avoided.
Page: NDA212725-90; NDA-212726-110, 111, 130, 131
minor
no
no
no
no
yes
yes
yes
yes (co-administration study)
Comment: When a single dose of 100 mg entrectinib is coadministered with strong CYP3A inhibitor itraconazole, AUClast and AUCINF of M5 were increased by 86% and 152%, respectively, while there was a 38% decrease of Cmax for M5. Coadministration of entrectinib (600 mg SD) with multiple doses of a strong CYP3A4 inducer rifampin (600 mg QD x 14 days) decreased the Cmax and AUCINF of M5 by 75% and 87%, respectively.
Page: NDA212726-114, 130, 131, 132
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
ALK inhibitors in non-small cell lung cancer: crizotinib and beyond.
2014 Jul
Entrectinib: a potent new TRK, ROS1, and ALK inhibitor.
2015
Activity of second-generation ALK inhibitors against crizotinib-resistant mutants in an NPM-ALK model compared to EML4-ALK.
2015 Jul
Patents

Sample Use Guides

600 mg orally daily per cycle (28 days). To be taken within 1 hour following a meal.
Route of Administration: Oral
In the CRC cell line KM12, which expresses the TPM3-TRKA, Entrectinib inhibited cell proliferation with an IC50 17 nM and completely inhibited TrkA phosphorylation at concentrations of 0.01uM and higher
Name Type Language
ENTRECTINIB
INN   USAN   WHO-DD  
USAN   INN  
Official Name English
ENTRECTINIB [USAN]
Common Name English
RXDX-101
Code English
BENZAMIDE, N-(5-((3,5-DIFLUOROPHENYL)METHYL)-1H-INDAZOL-3-YL)-4-(4-METHYL-1-PIPERAZINYL)-2-((TETRAHYDRO-2H-PYRAN-4-YL)AMINO)-
Systematic Name English
N-(5-(3,5-DIFLUOROBENZYL)-1H-INDAZOL-3-YL)-4-(4-METHYLPIPERAZIN-1YL)-2-(TETRAHYDRO-2H-PYRAN-4-YLAMINO)BENZAMIDE
Systematic Name English
ROZLYTREK
Brand Name English
ENTRECTINIB [WHO-DD]
Common Name English
ENTRECTINIB [ORANGE BOOK]
Common Name English
NMS-E628
Code English
ENTRECTINIB [INN]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C129825
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
FDA ORPHAN DRUG 462914
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
FDA ORPHAN DRUG 587117
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
FDA ORPHAN DRUG 462414
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
FDA ORPHAN DRUG 463014
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
NCI_THESAURUS C1967
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
Code System Code Type Description
FDA UNII
L5ORF0AN1I
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
PRIMARY
DRUG CENTRAL
5345
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
PRIMARY
DRUG BANK
DB11986
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
PRIMARY
INN
10132
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
PRIMARY
RXCUI
2197862
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
PRIMARY
PUBCHEM
25141092
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
PRIMARY
EVMPD
SUB177830
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
PRIMARY
ChEMBL
CHEMBL1983268
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
PRIMARY
NCI_THESAURUS
C114984
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
PRIMARY
CAS
1108743-60-7
Created by admin on Sat Jun 26 12:13:15 UTC 2021 , Edited by admin on Sat Jun 26 12:13:15 UTC 2021
PRIMARY