Pralatrexate is a chemotherapy drug used in the treatment of certain types of cancer. It is a folate analog metabolic inhibitor that interferes with the growth and replication of cancer cells. Pralatrexate is specifically approved for the treatment of a rare type of cancer called peripheral T-cell lymphoma (PTCL) in patients who have not responded well to other treatments or have relapsed after previous therapies.

Peripheral T-cell lymphoma is a type of non-Hodgkin lymphoma that affects T-cells, a type of white blood cell that plays a crucial role in the immune system. Pralatrexate works by inhibiting the enzyme dihydrofolate reductase, which is essential for the synthesis of DNA and other cellular components in rapidly dividing cells, including cancer cells.

Pralatrexate (Folotyn) is an anti-metabolite anticancer drug that has been approved for the treatment of refractory or relapsed T-cel lymphoma.

Pralatrexate Uses:

• Peripheral T-cell lymphoma:
  • Treatment of refractory or relapsed peripheral T-cell lymphoma (PTCL)
• Off Label Use of Pralatrexate in Adults:
  • Relapsed or refractory cutaneous T-cell lymphomas.

Pralatrexate dose in Adults

Note:

• Folic Acid: You should start taking folic acid 10 days before your first Pralatrexate dose. Take 1 to 1.25 milligrams (mg) of folic acid every day. Keep taking it while you're on Pralatrexate treatment and for 30 days after you've finished your last Pralatrexate dose.
• Vitamin B: Your doctor may also recommend vitamin B. You'll get 1,000 micrograms (mcg) of vitamin B through an injection (IM) within 10 weeks before your first Pralatrexate dose. After that, you'll get vitamin B injections every 8 to 10 weeks. You might get these on the same day as your Pralatrexate treatment.

Before you receive any dose of Pralatrexate, your doctor will check that:

• Your mouth and throat don't have severe inflammation (mucositis should be at a low level, called ≤ grade 1).
• Your white blood cell count (called absolute neutrophil count or ANC) is at least 1,000 per millimeter.
• Your platelet count is at least 100,000 per millimeter for the first dose and at least 50,000 per millimeter for later doses.

Pralatrexate dose in the treatment of relapsed or refractory Peripheral T-cell lymphoma (PTCL):

Dosing: Pralatrexate is administered intravenously (IV), which means it's delivered directly into your bloodstream through a vein.

• Dose Amount: The standard dose is 30 milligrams (mg) of Pralatrexate per square meter of your body's surface area.
• Frequency: You will receive this dose once a week.
• Duration: This treatment is given for a total of 6 weeks as part of a 7-week cycle. This means you will receive Pralatrexate once a week for 6 weeks, followed by a one-week break without treatment.
• Continuation: You will continue this treatment cycle until you experience disease progression (the cancer starts to grow again) or if you have unacceptable side effects that make it difficult to continue treatment.

Pralatrexate dose in the treatment of relapsed or refractory cutaneous T-cell lymphoma:

Dosing: Pralatrexate is administered intravenously (IV), which means it's delivered directly into your bloodstream through a vein.

• Dose Amount: The standard dose is 15 milligrams (mg) of Pralatrexate per square meter of your body's surface area.
• Frequency: You will receive this dose once a week.
• Duration: This treatment is given for a total of 3 weeks as part of a 4-week cycle. This means you will receive Pralatrexate once a week for 3 weeks, followed by a one-week break without treatment.

Pralatrexate dose in Childrens

Not indicated for use in children

Pregnancy Risk Factor D

• Studies on animals showed harmful effects on babies.
• If given to pregnant women, it might harm the baby.

Use of Pralatrexate while breastfeeding

• We don't know if pralatrexate passes into breast milk.
• Because it might harm a nursing baby, you should decide whether to stop breastfeeding or stop taking pralatrexate.
• Consider the benefits of the treatment for the mother.

Pralatrexate Dose in Kidney disease:

• If your kidney function (eGFR) is 30 mL/minute/1.73 m or more: You don't need to change the medicine dose.
• If your kidney function (eGFR) is between 15 to less than 30 mL/minute/1.73 m: Start with a lower dose of 15 mg/m. If you have side effects, the dose can be reduced further to 10 mg/m.
• If you have end-stage kidney disease (including if you're on dialysis): It's best to avoid this medicine unless the benefits are more important than the risks.

Pralatrexate Dose in Liver disease:

If you have liver issues:

• Patients with high bilirubin levels (>1.5 mg/dL), or high AST or ALT levels (more than 2.5 times the normal upper limit, or even more than 5 times if the liver is affected by lymphoma) were not included in the clinical studies.

If you see these liver problems persistently:

• Grade 3: If AST or ALT levels are between 5 to 20 times the normal limit, or if bilirubin is between 3 to 10 times the normal limit:
  • Skip the medicine dose.
  • When the levels come down to Grade 2 or lower, reduce the dose to 20 mg/m.
• Grade 4: If AST or ALT levels are more than 20 times the normal limit, or if bilirubin is more than 10 times the normal limit:
  • Stop the treatment completely.

Common Side Effects of Pralatrexate:

• Cardiovascular:
  • Edema
• Central Nervous System:
  • Fatigue
• Dermatologic:
  • Skin Rash
  • Pruritus
  • Night Sweats
• Endocrine & Metabolic:
  • Hypokalemia
• Gastrointestinal:
  • Mucositis
  • Nausea
  • Constipation
  • Vomiting
  • Diarrhea
  • Anorexia
  • Abdominal Pain
• Hematologic & Oncologic:
  • Thrombocytopenia
  • Anemia
  • Neutropenia
  • Leukopenia
• Hepatic:
  • Increased Serum Transaminases
• Infection:
  • Infection
• Neuromuscular & Skeletal:
  • Limb Pain
  • Back Pain
• Respiratory:
  • Cough
  • Epistaxis
  • Dyspnea
  • Pharyngolaryngeal Pain
• Miscellaneous:
  • Fever

Less Common Side Effects Of Pralatrexate:

• Cardiovascular:
  • Tachycardia
• Endocrine & Metabolic:
  • Severe Dehydration
• Hematologic & Oncologic:
  • Febrile Neutropenia
• Infection:
  • Sepsis
• Neuromuscular & Skeletal:
  • Weakness
• Respiratory:
  • Upper Respiratory Tract Infection

Contraindications to Pralatrexate:

In the manufacturer's instructions, there are no mentioned reasons to avoid the medicine.

However, in Canada, there's an extra warning: If you're allergic to pralatrexate or any ingredient in the medicine, you shouldn't take it. This warning isn't in the US instructions.

Warnings and precautions

Suppression of bone marrow

• It might lower platelet count (thrombocytopenia), white blood cell count (neutropenia), and red blood cell count (anemia).
• If these issues occur, you might need to adjust the dosage.
• It's important to regularly check your blood counts.
• Taking folic acid and vitamin B supplements can help lower the risk of these blood-related side effects.

Dermatologic reactions

• The medicine can cause serious and sometimes deadly skin reactions. This includes skin peeling, ulcers, and a condition called toxic epidermal necrolysis (TEN).
• These skin problems can get worse the longer you take the medicine.
• The skin reactions can also happen in areas where the lymphoma is affecting the skin and tissues below the skin.
• Keep a close eye on any skin changes. If you have a severe skin reaction, stop taking the medicine or speak to a doctor about pausing treatment.

Hepatotoxicity

• The medicine can cause liver problems or changes in liver tests.
• Regularly check how your liver is working with tests.
• If the liver tests stay abnormal, it might mean the medicine is harming your liver.
• This may require adjusting the dosage or even stopping the medicine.

Mucositis

• Pralatrexate can cause mucositis, which is inflammation of the mouth's lining and the digestive and urinary systems.
• Check weekly for signs of mucositis.
• If it occurs, the medicine dosage might need adjusting.
• Taking folic acid and vitamin B supplements can help reduce the risk of getting mucositis from the treatment.

Tumor lysis syndrome (TLS).

• Pralatrexate can lead to tumor lysis syndrome (TLS), which happens when tumor cells break down quickly.
• Watch closely for signs of TLS.
• If TLS occurs, treat the problems that come with it.

Renal impairment

• Patients with medium to severe kidney problems might have more medicine in their body, which can lead to more side effects.
• Regularly check how the kidneys are working and watch for side effects due to the increased amount of medicine in the body.
• If someone has severe kidney problems (eGFR between 15 to less than 30 mL/minute/1.73 m), the medicine dose should be adjusted.
• For patients with end-stage kidney disease (ESRD) or those on dialysis: Using this medicine can be risky.
• It has caused serious side effects like toxic epidermal necrolysis and mucositis in these patients. Avoid using it unless the benefits are higher than the risks.
• If taking pralatrexate with medicines that the kidneys clear out (like NSAIDs or sulfamethoxazole/trimethoprim), it might take longer for pralatrexate to leave the body.

Pralatrexate: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

Blood Tests:

• Complete Blood Count (CBC) with Differential
  • When: At the start and every week.
• Serum Chemistries
  • Focus on: Kidney and liver function tests.
  • When: Before the first and fourth doses in each treatment cycle.

Check for Mouth Issues:

• Mucositis Severity
  • When: At the start and every week.

Watch for Specific Problems:

• Tumor Lysis Syndrome: Look for signs that tumor cells are breaking down too quickly.
• Skin Issues: Keep an eye out for skin reactions or changes.

How to administer Pralatrexate?

• Method: IV push.
• Concentration: Use it undiluted.
• Duration: Push it into the IV over 3 to 5 minutes.
• Tip: Make sure it's injected into a line that has normal saline flowing freely.

Mechanism of action of Pralatrexate:

• Type: Antifolate analog.

Action:

• It enters cells that have less of a specific protein (reduced folate carrier, RFC-1).
• Inside the cell, it transforms into a different form with the help of folylpolyglutamate synthetase (FPGS).
• This transformed form then competes with a substance called DHFR for a place to bind.
• By doing this, it blocks DHFR, which is essential for DNA, RNA, and protein synthesis. This interruption in these processes can help treat certain conditions.

Distribution:

• S-diastereomer: 105 L
• R-diastereomer: 37 L

Protein Binding:

• About 67% of the drug binds to proteins in the blood.

Metabolism:

• The liver doesn't change it much. It doesn't really go through the usual phase I and phase II processes in the liver.

Half-life:

• It takes 12 to 18 hours for half of the drug to be eliminated from the body.

Excretion:

• The kidneys get rid of about 34% of the drug in the urine without changing its structure.

International Brands of Pralatrexate:

• Folotyn
• Difolta

Pralatrexate Brand Names in Pakistan:

Not available.