larotrectinib

Action and Spectrum

Actions and Spectrum: 

Actions: 

The mechanism of action of larotrectinib is to bind to the ATP-binding pocket of the TRK kinase domain, leading to the inhibition of the kinase activity of the TRK proteins. This inhibition prevents the activation of downstream signaling pathways, ultimately leading to tumor growth inhibition and apoptosis. 

Spectrum: 

larotrectinib has a broad spectrum of activity against various types of solid tumors, including lung cancer, thyroid cancer, colon cancer, gastrointestinal stromal tumors, sarcomas, and others, if they harbor the NTRK gene fusion. 

Drug Interaction

Adverse Reaction

Frequency defined:  

>10% 

Increased AST/ALT  

Anemia  

Fatigue  

Hypoalbuminemia  

Increased alkaline phosphatase  

Nausea  

Dizziness  

Vomiting  

Cough  

Constipation  

Neutropenia  

Diarrhea  

Pyrexia  

Dyspnea  

Peripheral edema  

Increased weight  

Headache  

Arthralgia  

Myalgia  

Muscular weakness  

Decreased appetite  

Abdominal pain  

Back pain  

Pain in extremity  

Hypertension   

1-10% 

Nasal congestion  

Fall  

Anemia 

Neutropenia 

Increased weight 

Fatigue 

Increased alkaline phosphatase 

Increased AST/ALT 

Diarrhea 

Dyspnea 

Decreased appetite 

Hypertension 

Hypoalbuminemia 

Pyrexia 

Nausea 

Vomiting 

Arthralgia 

Myalgia 

Back pain 

Pain in extremity 

Constipation 

Dizziness 

Black Box Warning

Contraindication / Caution

Contraindication/Caution: 

Contraindications: 

Hypersensitivity to larotrectinib or any of its components 

Cautions: 

• Hepatic impairment: larotrectinib is metabolized by the liver, so caution should be exercised when administering it to patients with moderate or severe hepatic impairment. These patients may require dose adjustments. 
• Pregnancy and lactation:  There are limited data on the use of larotrectinib in pregnant and breastfeeding women, and the potential risks to the fetus or infant are unknown. Therefore, larotrectinib should be used cautiously in these patients and only if the potential benefits outweigh the risks. 
• Drug interactions: larotrectinib is a substrate of CYP3A4 and CYP2C9, so caution should be exercised when co-administering it with potent inhibitors or inducers. Additionally, larotrectinib may increase the concentration of drugs that are substrates of CYP3A4 or P-glycoprotein, so concomitant use of such drugs should be monitored closely. 

Pregnancy / Lactation

Pregnancy consideration: The drug is toxic and unsafe for pregnant women and the developing fetus. 

Breastfeeding warnings: No data available regarding the excretion of larotrectinib in breast milk. Due to the possibility of serious adverse effects, women are advised to breastfeed one month after the last dose of larotrectinib. 

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: There is no affirmation of risk to the fetus found in animal reproduction studies, and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for a product in humans; Pregnant women must take care of the potential risks. 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms. However, despite potential dangers may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits. The drug is not for pregnant women. 
• Category N: No data is available for the drug under this category. 

Pharmacology

Pharmacology: 

larotrectinib is a selective small molecule inhibitor of tropomyosin receptor kinase (TRK) proteins, encoded by the NTRK genes (NTRK1, NTRK2, and NTRK3). Larotrectinib works by binding to the ATP-binding pocket of the TRK kinase domain, which leads to the inhibition of TRK kinase activity and subsequent inhibition of downstream signaling pathways activated by TRK proteins. 

Pharmacodynamics: 

The pharmacodynamics of larotrectinib involve inhibiting tropomyosin receptor kinase (TRK) proteins, encoded by the NTRK genes (NTRK1, NTRK2, and NTRK3). TRK proteins are receptor tyrosine kinases that play a critical role in the growth and survival of specific cancer cells. In tumors with an NTRK gene fusion, the TRK proteins are constitutively activated, activating downstream signaling pathways that promote tumor growth and survival. 

Pharmacokinetics: 

Absorption 

The steady state is reached in 3 days 

Peak plasma concentration is achieved in 1 hour 

The area under the curve is 4351 ng·hr/mL  

Bioavailability is 34% 

Distribution 

The volume of distribution at steady-state is 48L 

Protein-bound is 70% 

Metabolism 

The drug is metabolized mainly by CYP3A4 

Elimination and Excretion:  

The half-life is 2.9 hours 

The rate of clearance is 98 L/hr 

The drug is excreted 58% in feces and 39% in urine

Adminstartion

Administration: 

larotrectinib is available as capsules and an oral solution and is administered orally. The recommended dosage of larotrectinib is based on body weight and is administered twice daily. The capsules should be swallowed whole with water. The oral solution should be measured using a calibrated measuring device and swallowed directly or mixed with a small amount of water or apple juice. 

larotrectinib can be taken with or without food, but it is recommended to take it consistently concerning food. If a dose is missed, it should be taken as soon as possible, but if the next dose is due within 4 hours, the missed dose should be skipped, and the regular dosing schedule should be resumed. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: larotrectinib (Rx) 

Pronunciation: Lar-oh-trek-ti-nib 

Why do we use larotrectinib? 

larotrectinib is used to treat patients with solid tumors with an NTRK gene fusion, regardless of the tumor type or the patient’s age. NTRK gene fusions result from genetic alterations that lead to the abnormal fusion of the NTRK gene with another gene, resulting in the constitutive activation of TRK proteins. TRK proteins play a critical role in the growth and survival of certain types of cancer cells. 

larotrectinib is well-tolerated in clinical trials, with few side effects observed. Using larotrectinib may provide a new treatment option for patients with solid tumors with an NTRK gene fusion who have exhausted standard treatment options or have no effective treatment options available.