Antifolates

• Example of antifolates include methotrexate, pemetrexed, pralatrexate
• Methotrexate works by forming MTX-polyglutamate metabolites. This complex is selectively retained within the cancer cells for weeks and months.
• MOA of Methotrexate:

  1. high affinity towards DHFR catalytic site -> bind to DHFR
  2. depleting the intracellular pools of tetrahydrofolate (essential for thymidylate and purine nucleotides synthesis)
  3. interfere DNA synthesis
• PK of methotrexate:

  1. distributes widely in body tissue and total body water (therefore, caution in patients with pleural effusion & ascites)
  2. conventional dose - low CNS penetration
  3. maintain urine output >100mL/hr
  4. maintain urine pH > 7
• @ high dose of Methotrexate:

  1. concentration in renal tubules may exceed the amount that can be dissolved in urine
  2. MTX precipitate out of solution
  3. cause crystallization
  4. obstructs the tubule
  5. renal damage
• (Methotrexate): Maintain urine pH > 7

  1. add sodium bicarbonate (or) acetate to IV infusion
  2. give oral sodium bicarbonate (or) oral acetazolamide
• Methotrexate toxicities : schedule and dose dependent

  1. myelosuppression: nadir - 10 days, recovery - within 14-21 days
  2. mucositis: 3-5 days after treatment
  3. diarrhea
  4. N&V - dose dependent
  5. erythema,
  6. rash
  7. alopecia
  8. urticarial
  9. teratogenic - advice for contraception
• The side effects of methotrexate can be prevented/treated administering of leucovorin

  • derivatives of tetrahydrofolate
  • competes with MTX for active transport into cells
  • given AFTER MTX - given early may compromised antitumor efficacy
• Leucovorin:

  • started 24 hours after TX
  • after 24 hours, MTX toxicity may not be reversible with leucovorin
• Principle of high-dose Methotrexate:

  1. @high plasma levels - passive entry into tumor cells, can overcome the resistance, due to defective active transport
  2. increase free intracellular MTX levels - can overcome resistance secondary to high DHFR (or) altered enzyme binding
  3. prolonged plasma levels - by increase polyglutamate formation and prolongs the drug action
• Mechanism of Methotrexate resistance:

  1. decrease drug transport into cells
  2. decrease polyglutamate formation
  3. altered DHFR function
  4. increase levels of DHFR