Identification
- Summary
Larotrectinib is a kinase inhibitor used to treat solid tumors with neurotrophic receptor tyrosine kinase gene fusion, are metastatic, high risk for surgery, or have no alternative treatments.
- Brand Names
- Vitrakvi
- Generic Name
- Larotrectinib
- DrugBank Accession Number
- DB14723
- Background
Larotrectinib is an orally administered inhibitor of tropomyosin receptor kinase (Trk), a receptor tyrosine kinase activated by neurotrophins which is mutated in a variety of cancer cell types and plays an important role in tumor cell growth and survival.8 Upon administration, larotrectinib binds to Trk, thereby preventing neurotrophin-Trk interaction and Trk activation, which results in both the induction of cellular apoptosis and the inhibition of cell growth in tumors that overexpress Trk.8
Larotrectinib was granted accelerated approval by the FDA in November 2018 for the treatment of Trk-positive solid tumors. It was notable for being the second tissue-agnostic chemotherapy ever approved by the FDA.6
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Larotrectinib (DB14723)
- Weight
- Average: 428.444
Monoisotopic: 428.177230298 - Chemical Formula
- C21H22F2N6O2
- Synonyms
- Larotrectinib
- External IDs
- ARRY 470
- ARRY-470
- LOXO 101
- LOXO-101
Pharmacology
- Indication
Larotrectinib is a tyrosine kinase inhibitor that is currently indicated for the treatment of adult and pediatric patients with solid tumors that a) have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, b) are metastatic or where surgical resection is likely to result in severe morbidity, or c) have no satisfactory alternative treatments or that have progressed following treatment.7
These indications are approved under accelerated approval by the US FDA based on overall response rate and duration of response and continuation of support for these indications may be contingent upon the verification and description of continued clinical benefit in confirmatory trials.7
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Ntrk1 fusion positive •••••••••••• •••••• ••••••••• •••••••• •••••••• Treatment of Ntrk1 fusion positive •••••••••••• •••••• ••••••••• •••••••• •••••••• Treatment of Ntrk1 fusion positive •••••••••••• •••••• ••••••••• •••••••• •••••••• Treatment of Ntrk1 fusion positive •••••••••••• •••••• ••••••••• •••••••• •••••••• Treatment of Ntrk2 fusion positive •••••••••••• •••••• ••••••••• •••••••• •••••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
In a broad panel of purified enzyme assays, larotrectinib inhibited TRKA, TRKB, and TRKC with IC50 values between 5-11 nM.7 One other kinase, TNK2, was inhibited at approximately 100-fold higher concentration.7 At doses that are nine-fold greater than the recommended adult dose, larotrectinib does not elicit any QTc interval prolongation that is clinically relevant.7 No dose adjustment is recommended for patients with renal impairment of any severity,7 but dose reductions are warranted in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment.7
- Mechanism of action
Tropomysoin receptor kinases (TRK) like TRKA, TRKB, and TRKC elicit activities that regulate the natural growth, differentiation, and survival of neurons when they interact with endogenous neutrotrophin ligands.1,2,3,4,5 TRKA, TRKB, and TRKC are themselves encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively.1,2,3,4,5 It has been discovered that chromosomal rearrangements involving in-frame fusions of these genes with various partners, translocations in the TRK kinase domains, mutations in the TRK ligand-binding site, amplifications of NTRK, or the expression of TRK splice variants can result in constitutively-activated chimeric TRK fusion proteins that can act as oncogenic drivers that promote cell proliferation and survival in tumor cell lines.1,2,3,4,5,7
Subsequently, larotrectinib functions as an inhibitor of TRKs including TRKA, B, and C.1,2,3,4,5,7 In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression.1,2,3,4,5,7 Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R.7 Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.7
Target Actions Organism AHigh affinity nerve growth factor receptor inhibitorHumans ABDNF/NT-3 growth factors receptor inhibitorHumans ANT-3 growth factor receptor inhibitorHumans - Absorption
The mean absolute bioavailability of larotrectinib capsules is approximately 34% (range: 32-37%).7 In adult patients who received larotrectinib capsules 100 mg twice daily, Cmax was achieved at about one hour after dosing and steady-state was reached within three days.7 The mean steady-state Cmax and AUC0-24h of larotrectinib capsules was 788 ng/mL and 4351 ng*h/mL, respectively.7 In healthy subjects, the AUC of the larotrectinib oral solution was similar to that of the capsules and the Cmax was 36% greater with the oral solution.7
As compared to a fasted state, the administration of larotrectinib in healthy subjects alongside a high-fat meal resulted in a similar AUC and a reduction in Cmax of 35%.7
- Volume of distribution
Following intravenous administration to healthy subjects, the mean volume of distribution of larotrectinib at steady-state was approximately 48L.7
- Protein binding
Larotrectinib is 70% bound to human plasma proteins in vitro and binding is independent of drug concentration.7 The blood-to-plasma concentration ratio is 0.9.7
- Metabolism
Larotrectinib is metabolized predominantly by CYP3A4.7 Following oral administration of a single 100 mg dose of radiolabeled larotrectinib in healthy subjects, the major circulating drug components in plasma were unchanged larotrectinib (19%) and an O-linked glucuronide (26%).7
- Route of elimination
Following oral administration of a single 100 mg dose of radiolabeled larotrectinib in healthy subjects, 58% (5% unchanged) of the administered radioactivity was recovered in feces and 39% (20% unchanged) was recovered in urine.7
- Half-life
In healthy subjects, the half-life of larotrectinib following oral administration is 2.9 hours.7
- Clearance
The mean clearance CL/F of larotrectinib is 98 L/h.7
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Although there is no available data on larotrectinib use in pregnant women, based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and the agent's mechanism of action it is believed that larotrectinib can cause embryo-fetal harm when administered to a pregnant woman.7 Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.7 Furthermore, animal studies have revealed that lacrotrectinib can cross the placenta.7 Advise pregnant women of the potential risk to a fetus.7
Female patients of reproductive potential who are being treated with larotrectinib are advised to use effective contraception during larotrectinib treatment and for at least one week after the final dose.7 Males with female partners of reproductive potential are also advised to use effective contraception during larotrectinib therapy and for one week after the final dose.7
Carcinogenicity studies have not been conducted with larotrectinib.7 Larotrectinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or in the in vitro mammalian mutagenesis assays, with or without metabolic activation.7 In vivo, larotrectinib was negative in the mouse micronucleus test.7
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Larotrectinib can be increased when it is combined with Abametapir. Acetaminophen The serum concentration of Acetaminophen can be increased when it is combined with Larotrectinib. Ambroxol The risk or severity of methemoglobinemia can be increased when Larotrectinib is combined with Ambroxol. Amiodarone The metabolism of Larotrectinib can be decreased when combined with Amiodarone. Amprenavir The metabolism of Larotrectinib can be decreased when combined with Amprenavir. - Food Interactions
- Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of larotrectinib.
- Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of larotrectinib.
- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Larotrectinib sulfate RDF76R62ID 1223405-08-0 PXHANKVTFWSDSG-QLOBERJESA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Vitrakvi Capsule 25 mg/1 Oral Loxo Oncology, Inc. 2018-11-26 Not applicable US 
Vitrakvi Capsule 100 mg Oral Bayer Ag 2020-12-16 Not applicable EU 
Vitrakvi Solution 20 mg / mL Oral Bayer 2019-09-04 Not applicable Canada 
Vitrakvi Solution, concentrate 20 mg/1mL Oropharyngeal Bayer HealthCare Pharmaceuticals Inc. 2019-07-26 Not applicable US Vitrakvi Solution 20 mg/1mL Oral Loxo Oncology, Inc. 2018-11-26 Not applicable US
Categories
- ATC Codes
- L01EX12 — Larotrectinib
- Drug Categories
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Kinase Inhibitor
- P-glycoprotein substrates
- Protein Kinase Inhibitors
- Tropomyosin Receptor Kinases Inhibitors
- Tyrosine Kinase Inhibitors
- Classification
- Not classified
- Affected organisms
- Humans
Chemical Identifiers
- UNII
- PF9462I9HX
- CAS number
- 1223403-58-4
- InChI Key
- NYNZQNWKBKUAII-KBXCAEBGSA-N
- InChI
- 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
- IUPAC Name
- (3S)-N-{5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxypyrrolidine-1-carboxamide
- SMILES
- O[C@H]1CCN(C1)C(=O)NC1=C2N=C(C=CN2N=C1)N1CCC[C@@H]1C1=C(F)C=CC(F)=C1
References
- General References
- Berger S, Martens UM, Bochum S: Larotrectinib (LOXO-101). Recent Results Cancer Res. 2018;211:141-151. doi: 10.1007/978-3-319-91442-8_10. [Article]
- Drilon A, Nagasubramanian R, Blake JF, Ku N, Tuch BB, Ebata K, Smith S, Lauriault V, Kolakowski GR, Brandhuber BJ, Larsen PD, Bouhana KS, Winski SL, Hamor R, Wu WI, Parker A, Morales TH, Sullivan FX, DeWolf WE, Wollenberg LA, Gordon PR, Douglas-Lindsay DN, Scaltriti M, Benayed R, Raj S, Hanusch B, Schram AM, Jonsson P, Berger MF, Hechtman JF, Taylor BS, Andrews S, Rothenberg SM, Hyman DM: A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Cancer Discov. 2017 Sep;7(9):963-972. doi: 10.1158/2159-8290.CD-17-0507. Epub 2017 Jun 3. [Article]
- Fuse MJ, Okada K, Oh-Hara T, Ogura H, Fujita N, Katayama R: Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged Cancers. Mol Cancer Ther. 2017 Oct;16(10):2130-2143. doi: 10.1158/1535-7163.MCT-16-0909. Epub 2017 Jul 27. [Article]
- Doebele RC, Davis LE, Vaishnavi A, Le AT, Estrada-Bernal A, Keysar S, Jimeno A, Varella-Garcia M, Aisner DL, Li Y, Stephens PJ, Morosini D, Tuch BB, Fernandes M, Nanda N, Low JA: An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer Discov. 2015 Oct;5(10):1049-57. doi: 10.1158/2159-8290.CD-15-0443. Epub 2015 Jul 27. [Article]
- Vaishnavi A, Le AT, Doebele RC: TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015 Jan;5(1):25-34. doi: 10.1158/2159-8290.CD-14-0765. Epub 2014 Dec 19. [Article]
- Larotrectinib FDA Approval Press Release [Link]
- FDA Approved Drug Products: Vitrakvi (larotrectinib) capsules or solution for oral administration (November 2023) [Link]
- National Cancer Institute (NCI) Drug Dictionary: Larotrectinib sulfate [Link]
- External Links
- Human Metabolome Database
- HMDB0304896
- ChemSpider
- 44210503
- BindingDB
- 136597
- 2105628
- ChEMBL
- CHEMBL3889654
- ZINC
- ZINC000118399834
- Wikipedia
- Larotrectinib
- FDA label
- Download (528 KB)
- MSDS
- Download (200 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 100 mg Capsule Oral 100 mg/1 Capsule Oral 25 mg Capsule Oral 25 mg/1 Solution Oral 20 MG/ML Solution Oral 20 mg / mL Solution Oral 20 mg/1mL Solution, concentrate Oropharyngeal 20 mg/1mL Solution Oral 20 mg Capsule, coated Oral 100 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US10045991 No 2018-08-14 2037-04-04 US US10047097 No 2018-08-14 2029-10-21 US US9782414 No 2017-10-10 2035-11-16 US US8865698 No 2014-10-21 2029-10-21 US US9447104 No 2016-09-20 2029-10-21 US US10005783 No 2018-06-26 2029-10-21 US US9676783 No 2017-06-13 2029-10-21 US US8513263 No 2013-08-20 2029-12-23 US US9127013 No 2015-09-08 2029-10-21 US US10137127 No 2018-11-27 2037-04-04 US US10285993 No 2019-05-14 2035-11-16 US US10172861 No 2019-01-08 2035-11-16 US US10774085 No 2020-09-15 2029-10-21 US US10668072 No 2020-06-02 2037-04-04 US US10813936 No 2020-10-27 2035-11-16 US US10799505 No 2020-10-13 2036-08-15 US US11191766 No 2021-12-07 2037-04-04 US US11484535 No 2017-04-04 2037-04-04 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.238 mg/mL ALOGPS logP 2.07 ALOGPS logP 2.44 Chemaxon logS -3.3 ALOGPS pKa (Strongest Acidic) 10.94 Chemaxon pKa (Strongest Basic) 0.7 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 86 Å2 Chemaxon Rotatable Bond Count 3 Chemaxon Refractivity 122.96 m3·mol-1 Chemaxon Polarizability 41.61 Å3 Chemaxon Number of Rings 5 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 splash10-004i-0001900000-a714cdeef7c9e70af1ca Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-004i-1002900000-c230a7e2d2437bb9b32c Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-004i-0004900000-f3692f022953e93b90f3 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-01t9-2025900000-f86bb8c4e561dfe77532 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-017j-1469400000-07acdbee59e41f7d8145 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-03di-1489100000-b2d140f3ada85e073f32 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
- 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
- FDA Approved Drug Products: Vitrakvi (larotrectinib) capsules or solution for oral administration (November 2023) [Link]
- 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
- FDA Approved Drug Products: Vitrakvi (larotrectinib) capsules or solution for oral administration (November 2023) [Link]
- 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
- FDA Approved Drug Products: Vitrakvi (larotrectinib) capsules or solution for oral administration (November 2023) [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- FDA Approved Drug Products: Vitrakvi (larotrectinib) capsules or solution for oral administration (November 2023) [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- FDA Approved Drug Products: Vitrakvi (larotrectinib) capsules or solution for oral administration (November 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- ATP-binding cassette sub-family G member 2
- Molecular Weight
- 72313.47 Da
References
- FDA Approved Drug Products: Vitrakvi (larotrectinib) capsules or solution for oral administration (November 2023) [Link]
Drug created at November 29, 2018 17:47 / Updated at January 31, 2024 01:10