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 tropomyosin receptor kinase (Trk) inhibitor with demonstrated antineoplastic activity. 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. Trk, a receptor tyrosine kinase activated by neurotrophins, is mutated in a variety of cancer cell types and plays an important role in tumor cell growth and survival.
Originally discovered by Array BioPharma, the agent was ultimately licensed to Loxo Oncology in 2013. Larotrectinib is another example of innovative new cancer therapy medications that target key, specific genetic biomarker drivers of cancer rather than particular types of tumors 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 either 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, and c) have no satisfactory alternative treatments or that have progressed following treatment Label.
At the moment, these uses of larotrectinib are only approved under the auspices of an 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 Label.
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- Contraindications & Blackbox Warnings
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At doses that are nine-fold greater than the recommended adult dose, larotrectinib does not elicit any QTc interval prolongation that is clinically relevant Label.
- 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,Label.
Subsequently, larotrectinib functions as an inhibitor of TRKs including TRKA, B, and C 1,2,3,4,5,Label. 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,Label. Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R Label. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L Label.
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 has been recorded as 34%, from a range spanning 32% to 37% Label. In adult patients who received larotrectinib capsules 100 mg twice daily, peak plasma levels Cmax were achieved at about one hour after dosing and steady-state was reached within the time span of three days Label. The mean steady-state of these administered larotrectinib capsules was Cmax 788 ng/mL and the AUC(0-24hr) was 4351 ng*h/mL Label. Concurrently, in healthy subjects, the AUC of the administered larotrectinib oral solution formulation was similar to that of the capsules and the particular Cmax was 36% greater with the oral solution Label.
The AUC of larotrectinib was similar but the Cmax was reduced by 35% after oral administration of a single 100 mg capsule of larotrectinib to healthy subjects taken with a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to the Cmax and AUC in the fasted state Label.
- Volume of distribution
The mean volume of distribution Vss of larotrectinib has been documented as being 48L following intravenous administration in healthy subjects Label.
- Protein binding
Larotrectinib is approximately 70% bound to human plasma proteins in vitro and binding is independent of drug concentrations Label. The blood to plasma concentration ratio is 0.9 Label.
- Metabolism
Larotrectinib is metabolized predominantly by the CYP3A4 isoenzymes Label. Following oral administration of a single [14C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, unchanged larotrectinib constituted 19% and an O-linked glucuronide constituted 26% of the major circulating radioactive drug components in plasma Label.
- Route of elimination
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 Label.
- Half-life
The half-life of larotrectinib has been determined to be 2.9 hours Label.
- Clearance
The mean clearance CL/F of larotrectinib has been documented as 98 L/h Label.
- Adverse Effects
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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 Label. 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 Label. Furthermore, animal studies data note that lacrotrectinib can cross the placenta in animals Label. Advise pregnant women of the potential risk to a fetus Label.
There are no data on the presence of larotrectinib or its metabolites in human milk and no data on its effects on the breastfed child or on milk production Label. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with larotrectinib and for 1 week after the final dose Label.
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 Label. 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 Label.
Based on histopathological findings in the reproductive tracts of female rats in a 1-month repeated-dose study, larotrectinib use may reduce fertility in females Label.
The safety and effectiveness of larotrectinib in pediatric patients was established based upon data from clinical trials in adult or pediatric patients 28 days and older Label. The pharmacokinetics of larotrectinib in the pediatric population have also been determined to be similar to those seen in adults Label.
Clinical studies of larotrectinib did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects Label.
No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A). Larotrectinib clearance was reduced in subjects with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment Label.
No dose adjustment is recommended for patients with renal impairment of any severity Label.
Carcinogenicity studies have not been conducted with larotrectinib Label. 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 Label. In vivo, larotrectinib was negative in the mouse micronucleus test Label.
Fertility studies with larotrectinib have not been conducted. In a 3-month repeat-dose toxicity study in the rat, larotrectinib had no effects on spermatogenesis at 75 mg/kg/day (approximately 7 times the human exposure at the 100 mg twice daily dose) [FDA Label. Additionally, larotrectinib had no histological effects on the male reproductive tract in rats or monkeys at doses resulting in exposures up to 10 times the human exposure (AUC0-24hr) at the 100 mg twice daily clinical dose Label.
In a 1-month repeat-dose study in the rat, decreased uterine weight and uterine atrophy were seen at 200 mg/kg/day [approximately 45 times the human exposure (AUC) at the 100 mg twice daily dose] Label. Fewer corpora lutea and increased incidence of anestrus were also noted at doses ≥ 60 mg/kg/day (approximately 10 times the human exposure at the 100 mg twice daily dose] Label. There were no findings in female reproductive organs in repeat-dose studies in monkeys at exposures up to 22 times the human exposure at the 100 mg twice daily dose Label.
In a 1-month repeat-dose study in the rat, decreased uterine weight and uterine atrophy were seen at 200 mg/kg/day [approximately 45 times the human exposure (AUC) at the 100 mg twice daily dose] Label. Fewer corpora lutea and increased incidence of anestrus were also noted at doses ≥ 60 mg/kg/day (approximately 10 times the human exposure at the 100 mg twice daily dose) Label. Decreased fertility occurred in a juvenile animal study Label. There were no findings in female reproductive organs in repeat-dose studies in monkeys at exposures up to 22 times the human exposure at the 100 mg twice daily dose Label.
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Larotrectinib can be increased when it is combined with Abametapir. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Larotrectinib. Abrocitinib The serum concentration of Larotrectinib can be increased when it is combined with Abrocitinib. Acetaminophen The serum concentration of Acetaminophen can be increased when it is combined with Larotrectinib. Adagrasib The serum concentration of Larotrectinib can be increased when it is combined with Adagrasib. Afatinib The serum concentration of Larotrectinib can be increased when it is combined with Afatinib. Ambrisentan The serum concentration of Larotrectinib can be increased when it is combined with Ambrisentan. 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. 
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- 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 Solution 20 mg/ml Oral Bayer Ag 2021-05-25 Not applicable EU 
Vitrakvi Capsule 25 mg Oral Bayer Ag 2020-12-16 Not applicable EU Vitrakvi Capsule 25 mg/1 Oral Loxo Oncology, Inc. 2018-11-26 Not applicable US 
Vitrakvi Capsule 100 mg Oral Bayer 2020-11-13 Not applicable Canada 
Vitrakvi Solution 20 mg/1mL Oral Loxo Oncology, Inc. 2018-11-26 Not applicable US Vitrakvi Capsule 100 mg/1 Oral Bayer HealthCare Pharmaceuticals Inc. 2019-07-26 Not applicable US Vitrakvi Solution 20 mg/ml Oral Bayer Ag 2020-12-16 Not applicable EU Vitrakvi Solution, concentrate 20 mg/1mL Oropharyngeal Bayer HealthCare Pharmaceuticals Inc. 2022-12-06 Not applicable US Vitrakvi Capsule 25 mg Oral Bayer 2020-11-13 Not applicable Canada Vitrakvi Capsule 100 mg Oral Bayer Ag 2020-12-16 Not applicable EU
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 and other mammals
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]
- External Links
- ChemSpider
- 44210503
- BindingDB
- 136597
- 2105628
- ChEMBL
- CHEMBL3889654
- ZINC
- ZINC000118399834
- Wikipedia
- Larotrectinib
- FDA label
- Download (528 KB)
- MSDS
- Download (200 KB)
Clinical Trials
- Clinical Trials
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
- 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
- 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
- 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
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
Drug created at November 29, 2018 17:47 / Updated at October 03, 2023 16:58