Larotrectinib (Vitrakvi) inhibits tropomyosin kinase receptors TrkA, TrkB, and TrkC. It is indicated for the treatment of solid tumors that possess the NTRK (neurotrophic receptor tyrosine kinase) gene fusion.

Larotrectinib (Vitrakvi) Uses:

• Solid tumors [Ref]:

  • It is indicated in children and adult patients for the treatment of solid tumors that have an NTRK (neurotrophic receptor tyrosine kinase) gene fusion without a known acquired resistance mutation.
  • Eligible patients include metastatic disease or where surgical resection is not possible and may result in morbidity, patients win whom a satisfactory alternative treatment is not available, or in patients with disease progression with the treatment.

Larotrectinib (Vitrakvi) Dose in Adults:

Larotrectinib (Vitrakvi) Dose in the treatment of Solid tumors (with neurotrophic receptor tyrosine kinase [NTRK] gene fusion):

• 100 mg orally twice daily.
• Continue the treatment until either the disease progresses or unacceptable toxicity occurs.

• Dosage adjustment for CYP3A inhibitors/inducers:

  • Strong CYP3A4 inhibitors:
    • With strong CYP3A4 inhibitors, avoid using larotrectinib.
    • In patients with whom the drug can not be avoided, the dose of larotrectinib should be reduced by 50%.
    • After strong CYP3A4 inhibitors are discontinued, the dose of larotrectinib may be increased to the prior dose (after 3 to 5 elimination half-lives of the strong CYP3A4 inhibitor have elapsed).
  • Strong CYP3A4 inducers:
    • Avoid the use of concomitant larotrectinib with strong CYP3A4 inducers.
    • The dose of larotrectinib may be doubled if concomitant use with strong CYP3A4 inducers cannot be avoided.
    • The dose of larotrectinib may be reduced to the prior dose (after 3 to 5 elimination half-lives of the strong CYP3A4 inducer) when the strong CYP3A4 inducers are stopped.

  • Missed doses:

    • Do not make up for the missed dose it the next dose is scheduled within 6 hours.
    • Patients who vomit after the intake of the drug, the dose should not be repeated and taken at the scheduled time.

Larotrectinib (Vitrakvi) Dose in Childrens:

Note: Capsule and oral solution may be used interchangeably.

Larotrectinib (Vitrakvi) Dose in the treatment of unresectable or metastatic solid tumors with the presence of neurotrophic receptor tyrosine kinase (NTRK) gene fusion:

• Infants, Children, and Adolescents: Oral:

  • BSA <1 m² :
    • 100 mg/m²/dose two times a day.
    • Continue until the disease progresses or unacceptable toxicity
  • BSA ≥1 m²:
    • 100 mg two times a day.
    • Continue until the disease progresses or unacceptable toxicity

• Dosing adjustment for toxicity:

  • Grade 3 or 4 adverse reactions:
    • The treatment should be withheld until the adverse drug reactions improve and return to baseline or grade 1.
    • The dose may be modified when re-initiating the treatment if the adverse reactions resolve within four weeks.
    • If the adverse drug reactions take more than four weeks to resolve or return to grade 1, or if the patient is unable to tolerate after three-dose modifications, discontinue the treatment immediately.

• Dose modification:

  • First modification:

    • BSA <1 m²:
      • 75 mg/m²/dose two times a day
    • BSA ≥1 m²:
      • 75 mg two times a day

  • Second modification:

    • BSA <1 m²:
      • 50 mg/m²/dose two times a day
    • BSA ≥1 m²:
      • 50 mg two times a day.

  • Third modification:

    • BSA <1 m²:
      • 25 mg/m²/dose two times a day.
    • BSA ≥1 m²:
      • 100 mg once a day.

• Dosing adjustment for concomitant therapy:

  • Coadministration with strong CYP3A4 inhibitors:
    • With strong CYP3A4 inhibitors, avoid using larotrectinib.
    • In patients with whom the drug can not be avoided, the dose of larotrectinib should be reduced by 50%.
    • After strong CYP3A4 inhibitors are discontinued, the dose of larotrectinib may be increased to the prior dose (after 3 to 5 elimination half-lives of the strong CYP3A4 inhibitor have elapsed).
  • Strong CYP3A4 inducers:
    • Avoid the use of concomitant larotrectinib with strong CYP3A4 inducers.
    • The dose of larotrectinib may be doubled if concomitant use with strong CYP3A4 inducers cannot be avoided.
    • The dose of larotrectinib may be reduced to the prior dose (after 3 to 5 elimination half-lives of the strong CYP3A4 inducer) when the strong CYP3A4 inducers are stopped.

Pregnancy Risk Category: N (not assigned)

• Based on its mechanism of action, Larotrectinib could potentially cause harm to the foetus.
• TRK signaling disruption can lead to obesity, anhidrosis and developmental delays, cognitive impairment, cognitive impairment, insensitivity to pain, and cognitive impairment.
• All female patients with reproductive potential must have a pregnancy test performed before initiating treatment.
• Females should be advised of effective contraception during treatment and for one week following the last dose.
• Patients with female partners should be informed that effective contraception is available during and for the first week following the last dose.

Use of Larotrectinib while breastfeeding

• It is unknown if the drug will be excreted into breastmilk.
• Manufacturers recommend that you stop breastfeeding during treatment and for at least one week following the last dose.

Larotrectinib (Vitrakvi) Dose in Kidney Disease:

Adjustment in the dose is not necessary in patients with kidney disease.

Larotrectinib (Vitrakvi) Dose in Liver disease:

• Hepatic impairment prior to treatment initiation:

  • Mild hepatic impairment (Child-Pugh class A):
    • Adjustment in the dose is not necessary.
  • Moderate to severe hepatic impairment (Child-Pugh classes B and C):
    • Reduce the initial dose by 50%.

• Hepatotoxicity during treatment:

  • Grade 3 or 4 hepatic adverse reactions:
    • Withhold the treatment until the liver enzymes return to baseline or to grade 1.
    • Patients who develop hepatotoxicity within the first month may be started on reduced doses when the treatment is resumed.
    • Treatment may be permanently discontinued if the patient is unable to tolerate the drug after three dose reductions or if the liver enzymes do not return to baseline within four weeks of treatment discontinuation.

Common Side Effects of Larotrectinib (Vitrakvi):

• Cardiovascular:

  • Peripheral Edema
  • Hypertension

• Central nervous system:

  • Neurotoxicity
  • Fatigue
  • Dizziness
  • Headache
  • Myasthenia

• Endocrine & metabolic:

  • Hypoalbuminemia
  • Weight gain

• Gastrointestinal:

  • Nausea
  • Vomiting
  • Constipation
  • Diarrhea
  • Abdominal pain
  • Decreased appetite

• Hematologic & oncologic:

  • Anemia
  • Neutropenia

• Hepatic:

  • Increased serum alanine aminotransferase
  • Increased serum aspartate aminotransferase
  • Increased serum alkaline phosphatase

• Neuromuscular & skeletal:

  • Arthralgia
  • Myalgia
  • Back pain
  • Limb pain

• Respiratory:

  • Cough
  • Dyspnea

• Miscellaneous:

  • Fever

Less Common Side Effects of Larotrectinib (Vitrakvi):

• Central nervous system:

  • Falling
  • Delirium
  • Abnormal gait
  • Dysarthria
  • Paresthesia

• Respiratory:

  • Nasal congestion

Rare side effects of Larotrectinib (Vitrakvi):

• Cardiovascular:

  • Pericardial effusion
  • Syncope

• Central nervous system:

  • Cerebral edema
  • Memory impairment

• Dermatologic:

  • Cellulitis
  • Enterocutaneous fistula

• Endocrine & metabolic:

  • Dehydration
  • Hyponatremia
  • Increased amylase
  • Increased serum lipase

• Gastrointestinal:

  • Intestinal obstruction (small intestine)
  • Intestinal perforation

• Hematologic & oncologic:

  • Acute myelocytic leukemia

• Hepatic:

  • Jaundice

• Infection:

  • Sepsis

• Neuromuscular & skeletal:

  • Asthenia
  • Tremor

• Respiratory:

  • Pleural effusion

Contraindications to Larotrectinib (Vitrakvi):

• The manufacturer did not mention any contraindications.

Warnings and precautions

• Suppression of bone marrow

  • Treatment may be required to treat bone marrow suppression, which can manifest as anemia or neutropenia.

• Gastrointestinal toxicities:

  • Treatment may be necessary to prevent gastrointestinal toxicities. You may experience nausea, vomiting and constipation.

• Hepatotoxicity

  • Hepatotoxicity, manifesting in elevated liver enzymes, has been reported frequently. Although mild elevations of liver enzymes are not uncommon, they can be severe.
  • Hepatotoxicity can occur as soon as one month after treatment began or as late at 2.6 years.
  • It is possible to modify the dose or discontinue the drug permanently.
  • Patients should have their liver function tested every two weeks for the first month, then monthly thereafter. Then, as indicated by their doctor, they should be tested once a month.
  • Patients with severe or pre-existing hepatic impairments may be able to start on lower doses at first.

• Neurotoxicity:

  • Larotrectinib can cause neurologic toxicities, which may vary in severity.
  • Most patients experience neurotoxicity within the first three months of treatment.
  • Grade 3 neurologic adverse reactions include delirium and dizziness, dysarthrias, ataxia, paresthesia, and dysarthria. Grade 4 reactions are uncommon and include encephalopathy.
  • Grade 3 adverse reactions or higher may require dose modifications, including ataxia and delirium, dizziness, tremor, delirium and amnesia.
  • Patients and their families should be aware of possible neurotoxic effects.
  • Neurotoxic patients should be advised to refrain from driving and operating heavy machinery, which requires mental alertness.
  • Patients may require dose adjustment, temporary treatment interruption or discontinuation depending on how severe their neurotoxic symptoms are.

Larotrectinib: Drug Interaction

Monitoring parameters:

• Before initiating treatment, assess NTRK (neurotrophic receiver tyrosinekinase).
• Every two weeks, monitor liver function tests (ALT/AST) during the first month after treatment initiation.
• Then, every other month thereafter and as clinically indicated.
• Before initiating treatment, it is important to perform a pregnancy test on females with reproductive potential.
• Pay attention to signs and symptoms that could indicate neurotoxicity.
• Monitor compliance to treatment.
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How to administer Larotrectinib (Vitrakvi)?

• It should be administered orally with or without meals.
• The capsules should be swallowed whole with water. It should not be chewed or crushed.
• The oral solution should be properly measured with an oral syringe to ensure accurate dose adjustment.
• The capsule and oral solution can be used interchangeably.

Mechanism of action of Larotrectinib (Vitrakvi):

• Larotrectinib, a small-molecule inhibitor that is highly selective and potent against the three tropomyosin receptor (TRK) proteins TRKA, TRKB and TRKC, is highly selective.
• These proteins, i.e. TRKA, TRKB and TRKC are encoded in the neurotrophic receptor Tyrosine Kinase (NTRK), genes NTRK1, NTRK2, NTRK3, and NTRK4.
• The chimeric TRK-fusion proteins are sequentially activated by chromosomal alterations, including rearrangements or fusions of NTRK gene genes. 
• These proteins act as oncogenic drivers and promote cell proliferation and survival. Larotrectinib's anti-tumor activity is activated in cells that have constitutive activation TRK proteins.
• This can be caused by gene fusions, deletions of regulatory domains or cells with TRK overexpression.

Protein binding:

• 70% is bound to plasma proteins

Metabolism:

• It is metabolized in the liver primarily via CYP3A4 and forms an O-linked glucuronide metabolite

Bioavailability:

• Capsules: 34% (range: 32 to 37%)

Half-life elimination:

• 2.9 hours

Time to peak:

• ~1 hour

Excretion:

• Feces (58%; 5% unchanged);
• Urine (39%; 20% unchanged)

International Brands of Larotrectinib:

• Vitrakvi

Larotrectinib Brand Names in Pakistan:

No Brands Available in Pakistan.