Repotrectinib

Identification

Summary

Repotrectinib is a tyrosine kinase inhibitor used to treat locally active or metastatic non-small cell lung cancer

Brand Names

Augtyro

Generic Name

Repotrectinib

DrugBank Accession Number

DB16826

Background

Repotrectinib is a next-generation tyrosine kinase inhibitor (TKI) specifically designed to address resistance in the treatment of non-small cell lung cancer (NSCLC), specifically due to mutations in the ROS1 gene.¹ ROS1 mutations are one of the defined oncogenic drives of NSCLC, and the solvent-front mutation ROS1 G2032R is responsible for 50 to 60% of crizotinib-resistant cases.¹ Repotrectinib possesses a compact macrocyclic structure that both limits adverse interactions with resistance mutation hotspots and targets mutations in the solvent-front region.² Although resistance to multiple TKI has been reported, including crizotinib, lorlatinib, taletrectinib, and entrectinib, there has been no reported case of repotrectinib resistance.³

On November 15th, 2023, the FDA approved repotrectinib under the brand name Augtyro for the treatment of locally advanced or metastatic ROS1-Positive NSCLC. This approval is based on favorable results from the TRIDENT-1 study, where the objective response rate was 79% in TKI-naive patients and 38% in TKI-pretreated patients respectively.⁵

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Repotrectinib (DB16826)

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Weight

Average: 355.373
Monoisotopic: 355.144453003

Chemical Formula

C₁₈H₁₈FN₅O₂

Synonyms

• (3R,6S,)-45-FLUORO-3,6-DIMETHYL-5-OXA-2,8-DIAZA-1(5,3)-PYRAZOLO(1,5-A)PYRIMIDINA-4(1,2)-BENZENANONAPHAN-9-ONE
• (7S,13R)-11-Fluoro-7,13-Dimethyl-6,7,13,14-Tetrahydro-1,15-Ethenopyrazolo[4,3-F][1,4,8,10]Benzoxatriazacyclotridecin-4(5H)-One
• 1,15-ETHENO-1H-PYRAZOLO(4,3-F)(1,4,8,10)BENZOXATRIAZACYCLOTRIDECIN-4(5H)-ONE, 11-FLUORO-6,7,13,14-TETRAHYDRO-7,13-DIMETHYL-, (7S,13R)-
• Repotrectinib

External IDs

• TPX-0005

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Pharmacology

Indication

Repotrectinib is indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).⁴

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Locally advanced or metastatic non-small cell lung cancer		••••••••••••	•••••		•••••••

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Pharmacodynamics

Fusion proteins that include ROS1 domains can drive tumorigenic potential through the hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Repotrectinib exhibited anti-tumor activity in cultured cells expressing ROS1 fusions and mutations including SDC4-ROS1, SDC4-ROS1^G2032R, CD74-ROS1, CD74-ROS1^G2032R, CD74-ROS1^D2033N, and CD74-ROS1^L2026M.⁴

Repotrectinib exposure-response relationships and the time course of pharmacodynamic responses are not fully characterized. Repotrectinib does not cause a mean increase in the QTc interval > 20 milliseconds (ms) at 160 mg QD followed by 160 mg BID, the approved recommended dosage.⁴

Mechanism of action

Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and of the tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC.⁴

Target	Actions	Organism
AProto-oncogene tyrosine-protein kinase ROS	inhibitor	Humans
AHigh affinity nerve growth factor receptor	inhibitor	Humans
ABDNF/NT-3 growth factors receptor	inhibitor	Humans
ANT-3 growth factor receptor	inhibitor	Humans

Absorption

The geometric mean (CV%) of repotrectinib steady state peak concentration (C_max,ss) is 713 (32.5%) ng/mL and the area under the time concentration curve (AUC_0-24h,ss) is 7210 (40.1%) ng•h/mL following the approved recommended twice daily dosage in patients with cancer. Repotrectinib C_max and AUC_0-inf increases approximately dose-proportional (but less than linear with estimated slopes of 0.78 and 0.70, respectively) over the single dose range of 40 mg to 240 mg (0.25 to 1.5 times the approved recommended dosage). Steady-state PK was time-dependent with an autoinduction of CYP3A4. Steady-state is achieved within 14 days of daily administration of 160 mg.⁴

The geometric mean (CV%) absolute bioavailability of repotrectinib is 45.7% (19.6%). Peak repotrectinib concentration occurred at approximately 2 to 3 hours post a single oral dose of 40 mg to 240 mg (0.25 to 1.5 times the approved recommended dosage) under fasted conditions.⁴

No clinically significant differences in repotrectinib pharmacokinetics were observed in patients with cancer following administration of a high-fat meal (approximately 800-1000 calories, 50% fat).⁴

Volume of distribution

The geometric mean (CV%) apparent volume of distribution (Vz/F) was 432 L (55.9%) in patients with cancer following a single 160 mg oral dose of repotrectinib.⁴

Protein binding

Repotrectinib binding to plasma protein was 95.4% in vitro. The blood-to-plasma ratio was 0.56 in vitro.⁴

Metabolism

Repotrectinib is primarily metabolized by CYP3A4 followed by secondary glucuronidation.⁴

Route of elimination

Following a single oral 160 mg dose of radiolabeled repotrectinib, 4.84% (0.56% as unchanged) was recovered in urine and 88.8% (50.6% unchanged) in feces.⁴

Half-life

The repotrectinib mean terminal half-life is approximately 50.6 h for patients with cancer following a single dose. The steady-state repotrectinib terminal half-life is approximately 35.4 h for patients with cancer.⁴

Clearance

The geometric mean (CV%) apparent oral clearance (CL/F) was 15.9 L/h (45.5%) in patients with cancer following a single 160 mg oral dose of repotrectinib.⁴

Adverse Effects

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Toxicity

Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, repotrectinib can cause fetal harm when administered to a pregnant woman. There are no available data on repotrectinib use in pregnant women. Oral administration of repotrectinib to pregnant rats during the period of organogenesis resulted in fetal malformations at doses approximately 0.3 times the recommended dose of 160 mg twice daily based on BSA. Advise pregnant women of the potential risk to a fetus.⁴

Carcinogenicity studies with repotrectinib were not conducted. Repotrectinib was genotoxic in an in vitro assay in human lymphoblastoid TK6 cells and in an in vivo rat bone marrow micronucleus assay via an aneugenic mechanism of action. Repotrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.⁴

Dedicated fertility studies were not conducted with repotrectinib. There were no effects on male and female reproductive organs observed in general repeat-dose toxicology studies of up to 3 months in duration in rats and monkeys at any dose level tested, which equated to exposures of up to approximately 3 times the human exposure at the 160 mg twice daily dose based on AUC.⁴

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abacavir	The metabolism of Abacavir can be decreased when combined with Repotrectinib.
Abametapir	The serum concentration of Repotrectinib can be increased when it is combined with Abametapir.
Abemaciclib	The serum concentration of Abemaciclib can be decreased when it is combined with Repotrectinib.
Abrocitinib	The serum concentration of Repotrectinib can be increased when it is combined with Abrocitinib.
Acalabrutinib	The serum concentration of Acalabrutinib can be decreased when it is combined with Repotrectinib.

Food Interactions

• Take with or without food. Take repotrectinib at about the same time each day with or without food.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Augtyro	Capsule	40 mg/1	Oral	E.R. Squibb & Sons, L.L.C.	2023-12-05	Not applicable

Categories

Drug Categories

• BCRP/ABCG2 Inhibitors
• Cytochrome P-450 CYP2B6 Inducers
• Cytochrome P-450 CYP2B6 Inducers (strength unknown)
• Cytochrome P-450 CYP2C19 Inducers
• Cytochrome P-450 CYP2C19 Inducers (strength unknown)
• Cytochrome P-450 CYP2C8 Inducers
• Cytochrome P-450 CYP2C8 Inducers (strength unknown)
• Cytochrome P-450 CYP2C9 Inducers
• Cytochrome P-450 CYP2C9 Inducers (strength unknown)
• Cytochrome P-450 CYP3A Inducers
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inducers
• Cytochrome P-450 CYP3A4 Inducers (strength unknown)
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A5 Inhibitors
• Cytochrome P-450 CYP3A5 Inhibitors (strength unknown)
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Kinase Inhibitor
• MATE 2 Inhibitors
• MATE inhibitors
• OATP1B1/SLCO1B1 Inhibitors
• P-glycoprotein inhibitors
• P-glycoprotein substrates
• ROS1 tyrosine kinase inhibitors
• Tyrosine Kinase Inhibitors
• UGT1A1 Inhibitors

Classification

Not classified

Affected organisms

Not Available

Chemical Identifiers

UNII

08O3FQ4UNP

CAS number

1802220-02-5

InChI Key

FIKPXCOQUIZNHB-WDEREUQCSA-N

InChI

InChI=1S/C18H18FN5O2/c1-10-8-20-18(25)14-9-21-24-6-5-16(23-17(14)24)22-11(2)13-7-12(19)3-4-15(13)26-10/h3-7,9-11H,8H2,1-2H3,(H,20,25)(H,22,23)/t10-,11+/m0/s1

IUPAC Name

(3R,11S)-6-fluoro-3,11-dimethyl-10-oxa-2,13,17,18,21-pentaazatetracyclo[13.5.2.0^{4,9}.0^{18,22}]docosa-1(21),4,6,8,15(22),16,19-heptaen-14-one

SMILES

C[C@H]1CNC(=O)C2=C3N=C(N[C@H](C)C4=CC(F)=CC=C4O1)C=CN3N=C2

References

General References

1. Yun MR, Kim DH, Kim SY, Joo HS, Lee YW, Choi HM, Park CW, Heo SG, Kang HN, Lee SS, Schoenfeld AJ, Drilon A, Kang SG, Shim HS, Hong MH, Cui JJ, Kim HR, Cho BC: Repotrectinib Exhibits Potent Antitumor Activity in Treatment-Naive and Solvent-Front-Mutant ROS1-Rearranged Non-Small Cell Lung Cancer. Clin Cancer Res. 2020 Jul 1;26(13):3287-3295. doi: 10.1158/1078-0432.CCR-19-2777. Epub 2020 Apr 8. [Article]
2. Murray BW, Rogers E, Zhai D, Deng W, Chen X, Sprengeler PA, Zhang X, Graber A, Reich SH, Stopatschinskaja S, Solomon B, Besse B, Drilon A: Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations. Mol Cancer Ther. 2021 Dec;20(12):2446-2456. doi: 10.1158/1535-7163.MCT-21-0632. Epub 2021 Oct 8. [Article]
3. Keddy C, Shinde P, Jones K, Kaech S, Somwar R, Shinde U, Davare MA: Resistance Profile and Structural Modeling of Next-Generation ROS1 Tyrosine Kinase Inhibitors. Mol Cancer Ther. 2022 Feb;21(2):336-346. doi: 10.1158/1535-7163.MCT-21-0395. Epub 2021 Dec 14. [Article]
4. FDA Approved Drug Products: AUGTYRO™ (repotrectinib) capsules, for oral use (November 2023) [Link]
5. U.S. Food and Drug Administration Approves Augtyro™ (repotrectinib), a Next-Generation Tyrosine Kinase Inhibitor (TKI), for the Treatment of Locally Advanced or Metastatic ROS1-Positive Non-Small Cell Lung Cancer (NSCLC) [Link]

External Links

ChemSpider

64853849

BindingDB

374727

RxNav

2670644

ChEMBL

CHEMBL4298138

PDBe Ligand

7GI

Wikipedia

Repotrectinib

PDB Entries

7vkn / 7vko

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Recruiting	Treatment	Non-Small Cell Lung Carcinoma	1
2	Not Yet Recruiting	Treatment	Brain Metastases / Non-Small Cell Lung Cancer (NSCLC) / ROS1 Gene Rearrangement	1
1	Not Yet Recruiting	Treatment	Healthy Volunteers (HV) / Hepatic Impairment	1
1	Recruiting	Treatment	Advanced Solid Tumors / Metastatic Solid Neoplasm	1
1	Recruiting	Treatment	Non-Small Cell Lung Cancer (NSCLC)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	40 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US11452725	No	2016-07-24	2036-07-24
US10294242	No	2016-07-05	2036-07-05
US9714258	No	2015-01-23	2035-01-23

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0498 mg/mL	ALOGPS
logP	2.33	ALOGPS
logP	2.17	Chemaxon
logS	-3.8	ALOGPS
pKa (Strongest Acidic)	12.73	Chemaxon
pKa (Strongest Basic)	0.59	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	5	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	80.55 Å2	Chemaxon
Rotatable Bond Count	0	Chemaxon
Refractivity	106.42 m3·mol-1	Chemaxon
Polarizability	34.85 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4i-0009000000-8e86ccc2e0c0c9b8f3e3
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0udi-0009000000-6cc03be4048e601ec3f2
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0udi-0009000000-143d250914a0ce666d73
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4r-0009000000-4e8d6ff34732072dc3a9
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-014i-0009000000-9dce584a8df85e3d3a57
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0fg9-0019000000-a2eede4836ad77542a2b
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Details1. Proto-oncogene tyrosine-protein kinase ROS

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Orphan receptor tyrosine kinase (RTK) that plays a role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium. May activate several downstream signaling pathways related to cell differentiation, proliferation, growth and survival including the PI3 kinase-mTOR signaling pathway. Mediates the phosphorylation of PTPN11, an activator of this pathway. May also phosphorylate and activate the transcription factor STAT3 to control anchorage-independent cell growth. Mediates the phosphorylation and the activation of VAV3, a guanine nucleotide exchange factor regulating cell morphology. May activate other downstream signaling proteins including AKT1, MAPK1, MAPK3, IRS1 and PLCG2.

Specific Function

Atp binding

Gene Name

ROS1

Uniprot ID

P08922

Uniprot Name

Proto-oncogene tyrosine-protein kinase ROS

Molecular Weight

263912.88 Da

References

1. FDA Approved Drug Products: AUGTYRO™ (repotrectinib) capsules, for oral use (November 2023) [Link]

Details2. High affinity nerve growth factor receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Transmembrane receptor protein tyrosine kinase activity

Specific Function

Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympatheti...

Gene Name

NTRK1

Uniprot ID

P04629

Uniprot Name

High affinity nerve growth factor receptor

Molecular Weight

87496.465 Da

References

1. FDA Approved Drug Products: AUGTYRO™ (repotrectinib) capsules, for oral use (November 2023) [Link]

Details3. BDNF/NT-3 growth factors receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Protein homodimerization activity

Specific Function

Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differenti...

Gene Name

NTRK2

Uniprot ID

Q16620

Uniprot Name

BDNF/NT-3 growth factors receptor

Molecular Weight

91998.175 Da

References

1. FDA Approved Drug Products: AUGTYRO™ (repotrectinib) capsules, for oral use (November 2023) [Link]

Details4. NT-3 growth factor receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Receptor tyrosine kinase involved in nervous system and probably heart development. Upon binding of its ligand NTF3/neurotrophin-3, NTRK3 autophosphorylates and activates different signaling pathways, including the phosphatidylinositol 3-kinase/AKT and the MAPK pathways, that control cell survival and differentiation.

Specific Function

Atp binding

Gene Name

NTRK3

Uniprot ID

Q16288

Uniprot Name

NT-3 growth factor receptor

Molecular Weight

94427.47 Da

References

1. FDA Approved Drug Products: AUGTYRO™ (repotrectinib) capsules, for oral use (November 2023) [Link]

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Drug created at July 15, 2022 16:08 / Updated at February 23, 2024 01:08