Pexidartinib is a medication used for the treatment of certain rare diseases, specifically a type of noncancerous tumor known as tenosynovial giant cell tumor (TGCT) or pigmented villonodular synovitis (PVNS). TGCT/PVNS can occur in the synovium, which is the lining of joints, tendons, and bursae. These tumors can be locally aggressive and cause pain, stiffness, and limited joint mobility.

Pexidartinib works by inhibiting the activity of certain proteins called colony-stimulating factor 1 receptors (CSF1R) and KIT proto-oncogene receptor tyrosine kinase (KIT). These proteins are involved in the growth and development of TGCT/PVNS tumors. By targeting these proteins, pexidartinib can help reduce tumor size and alleviate symptoms associated with these rare tumors.

Turalio is the brand name of Pexidartinib. It is a Tyrosine kinase inhibitor and the first drug that has been approved for the treatment of tenosynovial giant cell tumor

Indications of Pexidartinib:

• Tenosynovial giant cell tumor:
  • It is indicated for treatment of symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery in adults.

Turalio (Pexidartinib) dose in adults:

Turalio (Pexidartinib) dose in the treatment of Tenosynovial giant cell tumor:

Regular Dose:

• Take 400 mg by mouth, two times a day.
• Continue this until the tumor stops responding or side effects become too strong.

If Taking Certain Other Drugs:

• There are some drugs (strong CYP3A inhibitors or UGT inhibitors) that can interfere with pexidartinib. Ideally, don't take them together. But if you must:
  • If you were taking 400 mg of pexidartinib two times a day, reduce it to 200 mg two times a day.
  • If you were taking 600 mg in total (200 mg in the morning and 400 mg at night), reduce to 200 mg two times a day.
  • If you were taking 200 mg two times a day, reduce it to 200 mg once a day.

After Stopping the Interfering Drug:

• If you stop the other drug (the CYP3A or UGT inhibitor), you can go back to your original pexidartinib dose. But wait until 3 times the half-life of that drug has passed.

Missed a Dose?

• If you miss a dose or throw up after taking it, just skip it. Take the next dose at the regular time.

Pexidartinib (Turalio) use in Children:

It has not been studied in children.

Turalio (Pexidartinib) Pregnancy Risk Category: U (Undefined)

• Pexidartinib might harm an unborn baby based on how it works and animal tests.
• Before starting the medicine, check if a woman can become pregnant.
• Women who can get pregnant should use birth control during treatment and for a month after the last dose.
• Men taking the medicine should use birth control if their partner can get pregnant, and continue for a week after their last dose.

Use of Pexidartinib while breastfeeding

• We're not sure if pexidartinib gets into breast milk.
• But because there's a chance it could harm a breastfed baby, the maker of the medicine advises against breastfeeding while taking it and for at least a week after the last dose.

Turalio (Pexidartinib) Dose adjustment in renal disease:

If you're measuring kidney function with the Cockcroft-Gault method:

• For a result of 15 to 89 mL/minute: Take a lower dose: 200 mg in the morning and 400 mg at night (600 mg in total for the day).

Also, if someone is on dialysis, pexidartinib likely won't be removed from the body because it sticks to proteins in the blood.

Turalio (Pexidartinib) Dose adjustment in liver disease:

Before Starting Pexidartinib Depending on Liver Function:

• Mild issues: No need to change the dose.
• Moderate or severe issues: No clear dose guidance from the manufacturer.
• Liver or bile disease: Avoid taking pexidartinib.

Changing Dose During Treatment If Liver Issues Appear:

• Usual dose: 800 mg/day (400 mg twice).
• First lower dose: 600 mg/day (200 mg in the morning, 400 mg at night).
• Second lower dose: 400 mg/day (200 mg twice). If this isn't tolerated, stop taking pexidartinib altogether.

Liver Enzymes (ALT & AST) Increase:

• 3-5 times the normal limit: Pause pexidartinib, check liver tests weekly. If they're within 3 times the normal limit within 4 weeks, resume with a reduced dose. If not, stop pexidartinib permanently.
• 5-10 times the normal limit: Pause pexidartinib, check liver tests two times a week. If within normal limits in 4 weeks, restart with a reduced dose. If not, stop pexidartinib permanently.
• Over 10 times the normal limit: Stop pexidartinib forever. Keep checking liver tests until they're lower.

Other Liver Tests (Alkaline Phosphatase & GGT) Increase:

• If both these tests are over twice the normal limit: Stop pexidartinib forever and regularly check liver tests until they go back to normal.

Bilirubin Increase:

• Slightly raised: Pause pexidartinib, check liver tests two times a week. If the levels are okay within 4 weeks, resume at a reduced dose. If not, stop pexidartinib forever.
• High levels: Stop pexidartinib forever and keep monitoring until levels are normal.

Common Side Effects of Pexidartinib:

• Cardiovascular:
  • Peripheral Edema
  • Hypertension
• Central Nervous System:
  • Fatigue
• Dermatologic:
  • Hair Discoloration
  • Skin Rash
  • Pruritus
• Endocrine & Metabolic:
  • Increased Lactate Dehydrogenase
  • Increased Serum Cholesterol
  • Decreased Serum Phosphate
• Gastrointestinal:
  • Dysgeusia
  • Vomiting
  • Decreased Appetite
  • Constipation
• Hematologic & Oncologic:
  • Decreased Neutrophils
  • Lymphocytopenia
  • Decreased Hemoglobin
  • Thrombocytopenia
• Hepatic:
  • Increased Serum Aspartate Aminotransferase
  • Increased Serum Alanine Aminotransferase
  • Increased Serum Alkaline Phosphatase
• Ophthalmic:
  • Swelling Of Eye

Uncommon Side Effects Of Turalio (Pexidartinib):

• Central Nervous System:
  • Neuropathy
  • Cognitive Dysfunction
• Dermatologic:
  • Alopecia
  • Dyschromia
• Gastrointestinal:
  • Cholangitis
  • Oral Mucosa Ulcer
  • Stomatitis
  • Xerostomia
• Hepatic:
  • Hepatotoxicity
  • Increased Serum Bilirubin
  • Hepatic Disease
• Ophthalmic:
  • Blurred Vision
  • Decreased Visual Acuity
  • Diplopia
  • Photophobia
• Miscellaneous:
  • Fever

Rare side effects of Turalio:

• Central Nervous System:
  • Dizziness
• Endocrine & Metabolic:
  • Increased Gamma-Glutamyl Transferase
• Gastrointestinal:
  • Abdominal Pain
  • Nausea

Contraindications to Turalio (Pexidartinib):

• The manufacturer's label for pexidartinib doesn't list any specific conditions where the medication should not be used (contraindications).
• However, it's important to note that the absence of contraindications in the label doesn't mean the medication is suitable for everyone.

Warnings and precautions

Hepatotoxicity: [US Boxed Warning]

• The use of pexidartinib comes with a serious warning related to potential liver problems.
• This medication can cause severe and even fatal liver injury.
• Before starting pexidartinib and while taking it, your doctor will closely monitor your liver function.
• If there are signs of liver issues, treatment with pexidartinib may need to be paused, the dose reduced, or the medication stopped permanently.
• Some cases of liver injury caused by pexidartinib have been very severe, including ductopenia and cholestasis, and in rare cases, they have been fatal or required a liver transplant.
• It's not possible to predict who might experience these liver problems, and the exact cause is unknown.
• It's important to avoid pexidartinib if you have certain liver conditions or elevated liver enzymes, and your liver function will be regularly checked during treatment.
• Pexidartinib should be taken on an empty stomach to reduce the risk of liver issues, and the concurrent use of other medications that can harm the liver should be avoided if you have liver problems or elevated liver markers.

Renal impairment

• For patients with kidney problems, a reduced dose of pexidartinib is advised.

Pexidartinib: Drug Interaction

Monitoring parameters:

• Liver Function Tests:
  • Before starting pexidartinib.
  • Weekly for the first 8 weeks.
  • Every 2 weeks for the next month.
  • Every 3 months after that.
  • If pexidartinib is restarted (rechallenge), check weekly for the first month.
• Kidney Health:
  • Regularly check how the kidneys are working.
• Pregnancy Status:
  • For women who can become pregnant, make sure to check if they're pregnant before starting the medication.
• Liver Injury Signs:
  • Watch out for symptoms indicating liver problems.
• Medication Adherence:
  • Keep track of whether the patient is taking the medication as prescribed.

How to administer Turalio (Pexidartinib)?

Empty Stomach:

• Take the medicine at least 1 hour before eating or 2 hours after eating a meal or snack.
• Swallow the capsules whole. Don’t open, break, or chew them.

If Using Acid-Reducing Agents:

• Antacids: Take pexidartinib either 2 hours before or 2 hours after these.
• H2-Receptor Antagonists: Take pexidartinib more than 2 hours before or 10 hours after these.
• Proton Pump Inhibitors: It's best not to take pexidartinib with these at all.

Mechanism of action of Pexidartinib (Turalio):

• Pexidartinib is a type of medication called a "tyrosine kinase inhibitor."
• It mainly targets a specific receptor called the "colony-stimulating factor 1 receptor" (CSF1R). It's very good at blocking this receptor.
• Pexidartinib also affects other receptors like KIT and FLT3-internal tandem duplication (FLT3-ITD).
• When CSF1R's partner molecule is overactive, it can lead to more cells growing and gathering in the synovium (a tissue in joints).
• Pexidartinib stops the growth of cells that rely on CSF1R to grow.

Distribution:

• Volume of Distribution (V/F): 187 liters. This tells us about the space in the body the drug spreads to.

Protein Binding:

• Over 99% of the drug binds to proteins in the blood, specifically to albumin and alpha-1 acid glycoprotein.

Metabolism:

• The body breaks down pexidartinib mainly in two ways:
  • Oxidation using an enzyme called CYP3A4.
  • Glucuronidation using UGT1A4. This process forms an inactive by-product.

Half-life Elimination:

• About 26.6 hours. This is the time it takes for half of the drug to be removed from the body.

Peak Time:

• The highest level of the drug in the body is reached in about 2.5 hours after taking it.

Excretion:

• How the drug leaves the body:
  • Feces: 65% (with 44% as the unchanged drug).
  • Urine: 27% (as by-products).

Clearance Rate:

• 5.1 liters per hour. This measures how fast the drug is removed from the body.

International Brands of Pexidartinib:

• Turalio

Pexidartinib Brand Names in Pakistan:

Not available.