Pralatrexate – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

The selectivity of pralatrexate for cancer cells is based upon the observation that cancer cells generally have overexpression of reduced folate carrier protein-1 (RTC-1) compared to normal somatic cells. This carrier protein allows the entrance of pralatrexate into the cell. Upon entering the cell, folypolyglutamate synthase FPGS catalyzes the polyglutamylation of pralatrexate so that it is retained inside the cell. Once inside, pralatrexate competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase. Subsequent depletion of thymidine monophosphate (TMP) occurs so that the cancer cell is unable to synthesize DNA and RNA. As a result, the cancer cell cannot proliferate and is forced to undergo apoptosis. Pralatrexate is more effective against cells that are actively dividing.

Pralatrexate is a folate analog metabolic inhibitor that competitively inhibits dihydrofolate reductase. It is also a competitive inhibitor for polyglutamylation by the enzyme folylpolyglutamyl synthetase. This inhibition results in the depletion of thymidine and other biological molecules the synthesis of which depends on single carbon transfer.


This study evaluated mechanistic differences between pralatrexate, methotrexate, and pemetrexed. Inhibition of dihydrofolate reductase (DHFR) was quantified using recombinant human DHFR. Cellular uptake and folylpolyglutamate synthetase (FPGS) activity were determined using radiolabeled pralatrexate, methotrexate, and pemetrexed in NCI-H460 non-small cell lung cancer (NSCLC) cells. The tumor growth inhibition (TGI) was assessed using MV522 and NCI-H460 human NSCLC xenografts. Apparent K ( i ) values for DHFR inhibition were 45, 26, and >200 nM for pralatrexate, methotrexate, and pemetrexed, respectively. A significantly greater percentage of radiolabeled pralatrexate entered the cells and was polyglutamylatated relative to methotrexate or pemetrexed. In vivo, pralatrexate showed superior anti-tumor activity in both NSCLC models, with more effective dose-dependent TGI in the more rapidly growing NCI-H460 xenografts. Pralatrexate demonstrated a distinct mechanistic and anti-tumor activity profile relative to methotrexate and pemetrexed. Pralatrexate exhibited enhanced cellular uptake and increased polyglutamylation, which correlated with increased TGI in NSCLC xenograft models.


  • Treatment of relapsed or refractory peripheral T-cell lymphoma.
  • Treatment of peripheral T-cell lymphoma,
  • Pralatrexate is a parenterally administered folate antagonist and antineoplastic agent, used in the treatment of peripheral T-cell lymphomas.
  • Pralatrexate is approved to treat: Peripheral T-cell lymphoma in patients whose disease is refractory (does not respond to treatment) or has recurred (come back).
  • Pralatrexate is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is based on the overall response rate.
  • Cutaneous T Cell Lymphomas (CTCL)
  • Relapsed Peripheral T-Cell Lymphoma
  • Refractory Peripheral T-cell Lymphoma Unspecified

Use in Cancer

Pralatrexate is approved to treat:

This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, confirmatory trial(s) must show that pralatrexate provides a clinical benefit in these patients.

Pralatrexate is also being studied in the treatment of other types of cancer.


  • Anemia, neutropenia, thrombocytopenia. Hematologic toxicity (e.g., thrombocytopenia, neutropenia, and anemia) has been reported with pralatrexate therapy
  • Renal disease, renal impairment
  • Hepatic disease
  • Oral ulceration
  • Tumor lysis syndrome (TLS)
  • Serious rash.
  • Geriatric.
  • Pregnancy.
  • anemia
  • decreased blood platelets
  • low levels of a type of white blood cell called neutrophils
  • stomatitis, is a condition with painful swelling and sores inside the mouth
  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • moderate to severe kidney impairment


Strengths: 20 mg/mL


  • Usual Adult Dose: 30 mg/m2 via intravenous push over 3 to 5 minutes once weekly for 6 weeks in 7-week cycles.
  • Duration: Until disease progression or unacceptable toxicity.
  • Patients should take low doses (1 mg to 1.25 mg) of oral folic acid daily.
  • Folic acid should start 10 days before the first dose of pralatrexate and continue for 30 days after the last dose.
  • Patients should also receive a B12 (1 mg) injection within 10 weeks before the first dose of pralatrexate and every 8 to 10 weeks thereafter.
  • Subsequent B12 injections may be given the same day as treatment with pralatrexate

Dose Adjustments

  • Management of severe or intolerable adverse reactions may require dose omission, reduction, or interruption of pralatrexate therapy.
  • Doses may be omitted or reduced based on patient tolerance. Omitted doses will not be made up at the end of the cycle. Once a dose reduction occurs for toxicity, do not re-escalate.

Dose Modifications for Mucositis:

  • A) If mucositis is grade 2 on the day of treatment, omit the dose. Upon recovery to grade 1 or less, continue the prior dose.
  • B) If mucositis is a recurrence of grade 2 on the day of treatment, omit the dose. Upon recovery to grade 1 or less, treatment may be resumed at 20 mg/m2.
  • C) If mucositis is grade 3 on the day of treatment, omit the dose. Upon recovery to grade 1 or less, treatment may be resumed at 20 mg/m2.
  • D) If mucositis is grade 4 on the day of treatment, therapy should be discontinued.

Dose Modifications for Hematologic Toxicities:
1) Blood count on day of treatment reveals a platelet less than 50,000/mcL:

  • A) If the duration of the toxicity is 1 week, omit the dose. Upon restart, continue the prior dose.
  • B) If the duration of the toxicity is 2 weeks, omit the dose. Upon restart, treatment may be resumed at 20 mg/m2.
  • C) If the duration of the toxicity is 3 weeks, therapy should be discontinued.

2) ANC is 500 to 1,000/mcL and no fever:

  • If the duration of the toxicity is 1 week, omit the dose. Upon restart, continue the prior dose.

3) ANC 500 to 1,000/mcL with fever or ANC less than 500/mcL:

  • A) If the duration of the toxicity is 1 week, omit the dose and give G-CSF or GM-CSF support. Upon restart, continue the prior dose with G-CSF or GM-CSF support.
  • B) If the duration of the toxicity is 2 weeks or a recurrence, omit the dose and give G-CSF or GM-CSF support. Upon restart, treatment may be resumed at 20 mg/m2 with G-CSF or GM-CSF support.
  • C) If the duration of the toxicity is 3 weeks or a second recurrence, therapy should be discontinued.

4) Dose modifications for all other treatment-related toxicities:

  • A) If the toxicity is grade 3, omit the dose. Upon restart, treatment may be resumed at 20 mg/m2.
  • B) If toxicity is grade 4, therapy should be discontinued.

Administration advice:
Prior to administering any dose of pralatrexate:

  • 1) Mucositis should be grade 1 or less.
  • 2) The platelet count should be greater than or equal to 100,000/mcL for the first dose and greater than or equal to 50,000/mcL for all subsequent doses.
  • 3) The absolute neutrophil count (ANC) should be greater than or equal to 1,000/mcL.

Side Effects

The Most Common

  • nausea
  • vomiting
  • diarrhea
  • constipation
  • decreased appetite
  • tiredness
  • weakness
  • rash
  • itching
  • night sweats
  • stomach, back, arm, or leg pain
  • swelling of the hands, feet, ankles, or lower legs
  • white patches or sores on the lips or in the mouth and throat
  • fever, sore throat, cough, chills, or other signs of infection
  • unusual bleeding or bruising
  • bleeding gums
  • nosebleeds
  • small red or purple dots on the skin
  • blood in the urine or stool
  • shortness of breath
  • chest pain
  • fast or irregular heartbeat
  • pale skin
  • cold hands and feet
  • extreme thirst
  • dry, sticky mouth
  • sunken eyes
  • decreased urination
  • dizziness or lightheadedness

More common

  • Black, tarry stools
  • bleeding gums
  • blood in the urine or stools
  • body aches or pain
  • chills
  • convulsions
  • cough
  • cracked lips
  • decreased urine
  • diarrhea
  • difficult or labored breathing
  • difficulty with swallowing
  • dry mouth
  • ear congestion
  • fast, pounding, or irregular heartbeat or pulse
  • fever
  • headache
  • increased thirst
  • loss of appetite
  • loss of voice
  • lower back or side pain
  • mood changes
  • muscle pain or cramps
  • nasal congestion
  • nausea or vomiting
  • numbness or tingling in the hands, feet, or lips
  • painful or difficult urination
  • pale skin
  • pinpoint red spots on the skin
  • runny nose
  • shortness of breath
  • sneezing
  • sore throat
  • sores, ulcers, or white spots on the lips, tongue, or inside the mouth
  • swelling
  • tightness in the chest
  • troubled breathing with exertion
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • Abdominal or stomach pain
  • back pain
  • bloody nose
  • constipation
  • itching skin
  • lack or loss of strength
  • night sweats
  • pain in the arms or legs
  • rash
  • weight loss

Drug Interactions

Pregnancy and Lactation

FDA Pregnancy Category D 


FOLOTYN can cause fetal harm when administered to a pregnant woman. Pralatrexate was embryotoxic and fetotoxic in rats at IV doses of 0.06 mg/kg/day (0.36 mg/m2/day or about 1.2% of the clinical dose on an mg/m2 basis) given on gestation days 7 through 20. Treatment with pralatrexate caused a dose-dependent decrease in fetal viability manifested as an increase in late, early, and total resorptions. There was also a dose-dependent increase in post-implantation loss. In rabbits, IV doses of 0.03 mg/kg/day (0.36 mg/m2 /day) or greater given on
gestation days 8 through 21 also caused abortion and fetal lethality. This toxicity manifested as early and total resorptions, post-implantation loss, and a decrease in the total number of live fetuses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.


It is not known whether pralatrexate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from this drug, a decision should be made whether to discontinue nursing or to discontinue FOLOTYN, taking into account the importance of FOLOTYN to the mother.

How should this medicine be used?

Pralatrexate injection comes as a solution (liquid) to be injected intravenously (into a vein) by a doctor or nurse in a hospital or clinic. It is usually given over a period of 3 to 5 minutes once a week for 6 weeks as part of a 7-week cycle. Your treatment will probably continue until your condition worsens or you develop serious side effects.

Your doctor may need to adjust your dose, skip a dose, or stop your treatment if you experience certain side effects. Be sure to tell your doctor how you are feeling during your treatment with a pralatrexate injection.

You will need to take folic acid and vitamin B12 during your treatment with pralatrexate injection to help prevent certain side effects. Your doctor will probably tell you to take folic acid by mouth every day beginning 10 days before you start your treatment and for 30 days after your final dose of pralatrexate injection. Your doctor will also probably tell you that you will need to receive a vitamin B12 injection no more than 10 weeks before your first dose of pralatrexate injection and every 8 to 10 weeks for as long as your treatment continues.

What special precautions should I follow?

Before receiving a pralatrexate injection,

  • tell your doctor and pharmacist if you are allergic to pralatrexate injection, any other medications, or any of the ingredients in pralatrexate injection. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: aspirin and other nonsteroidal anti-inflammatory medications (NSAIDs) such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn); probenecid (Probalan), and trimethoprim/sulfamethoxazole (Bactrim). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had kidney or liver disease.
  • tell your doctor if you are pregnant, could be pregnant, or plan to become pregnant. You should not become pregnant while you are receiving pralatrexate injections. Talk to your doctor about birth control methods that you can use during your treatment. If you become pregnant while receiving a pralatrexate injection, call your doctor immediately. Pralatrexate injection may harm the fetus.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are receiving a pralatrexate injection.


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