DESCRIPTION
Mechanism of Action
• Cell cycle–specific antifolate analog, active in S-phase of the cell
cycle.
• Enters cells through specific transport systems mediated by the
reduced folate carrier and the folate receptor protein.
• Requires polyglutamation by the enzyme folylpolyglutamate synthase
(FPGS) for its cytotoxic activity.
• Inhibition of dihydrofolate reductase (DHFR) resulting in depletion
of critical reduced folates.
• Inhibition of de novo thymidylate synthesis.
• Inhibition of de novo purine synthesis.
• Incorporation of dUTP into DNA resulting in inhibition of DNA synthesis
and function.
Mechanism of Resistance
• Increased expression of the target enzyme DHFR through either
gene amplification or increased transcription, translation, and/or
post-translational events.
• Alterations in the binding affinity of DHFR for methotrexate.
• Decreased carrier-mediated transport of drug into cell through
decreased expression and/or activity of reduced folate carrier (RFC)
or folate-receptor protein (FRP).
• Decreased formation of cytotoxic MTX polyglutamates through either
decreased expression of FPGS or increased expression of γ-glutamyl
hydrolase (GGH).
• Decreased expression of mismatch repair enzymes may contribute to
drug resistance.
Absorption
Oral bioavailability is saturable and erratic at doses greater than 25 mg/m2.
Peak serum levels are achieved within 1–2 hours of oral administration.
Methotrexate is completely absorbed from parenteral routes of administration,
and peak serum concentrations are reached in 30–60 minutes after IM
injection.
Distribution
Widely distributed throughout the body. At conventional doses, CSF levels
are only about 5%–10% of those in plasma. High-dose MTX yields therapeutic
concentrations in the CSF. Distributes into third-space fluid collections
such as pleural effusion and ascites. Only about 50% of drug bound to
plasma proteins, mainly to albumin.
Metabolism
Extensive metabolism in liver and in cells by FPGS to higher polyglutamate
forms. About 10%–20% of parent drug and the 7-hydroxymetabolite
are eliminated in bile and then reabsorbed via enterohepatic circulation.
Renal excretion is the main route of elimination and is mediated by glomerular
filtration and tubular secretion. About 80%–90% of an administered
dose is eliminated unchanged in urine within 24 hours. Terminal
half-life of drug is on the order of 8–10 hours.
Indications
1. Breast cancer.
2. Head and neck cancer.
3. Osteogenic sarcoma.
4. Acute lymphoblastic leukemia.
5. Non-Hodgkin’s lymphoma.
6. Primary CNS lymphoma.
7. Meningeal leukemia and carcinomatous meningitis.
8. Bladder cancer.
9. Gestational trophoblastic cancer.
Dosage Range
1. Low dose: 10–50 mg/m2 IV every 3–4 weeks.
2. Low dose weekly: 25 mg/m2 IV weekly.
3. Moderate dose: 100–500 mg/m2 IV every 2–3 weeks.
4. High dose: 1–12 grams/m2 IV over a 3- to 24-hour period every 1–3
weeks.
5. Intrathecal: 10–15 mg IT two times weekly until CSF is clear, then
weekly dose for 2–6 weeks, followed by monthly dose.
6. Intramuscular: 25 mg/m2 IM every 3 weeks.
Drug Interaction 1
Aspirin, penicillins, probenecid, nonsteroidal anti-inflammatory agents,
and cephalosporins—These drugs inhibit the renal excretion of methotrexate
leading to enhanced drug effect and toxicity.
Drug Interaction 2
Warfarin—Methotrexate may enhance the anticoagulant effect of warfarin
through competitive displacement from plasma proteins.
Drug Interaction 3
5-Fluorouracil—Methotrexate enhances the antitumor activity of 5-
fluorouracil when given 24 hours before fluoropyrimidine treatment.
Drug Interaction 4
Leucovorin—Leucovorin rescues the toxic effects of methotrexate and
may also impair the antitumor activity. The active form of leucovorin is the
L-isomer.
Drug Interaction 5
Thymidine—Thymidine rescues the toxic effects of methotrexate and
may also impair the antitumor activity.
Drug Interaction 6
Folic acid supplements—These supplements may counteract the antitumor
effects of methotrexate and should be discontinued while on therapy.
Drug Interaction 7
Proton pump inhibitors—Proton pump inhibitors may reduce the elimination
of methotrexate, which can then result in increased serum methotrexate
levels, leading to increased toxicity. This is an especially important issue
for patients receiving high-dose methotrexate.
Drug Interaction 8
L-Asparaginase—L-Asparaginase antagonizes the antitumor activity of
methotrexate.
Special Considerations
1. Use with caution in patients with abnormal renal function. Dose
should be reduced in proportion to the creatinine clearance.
Important to obtain baseline creatinine clearance and to monitor
renal status during therapy.
2. Instruct patients to stop folic acid supplements during therapy as
they may counteract the effects of methotrexate.
3. Monitor CBCs on a weekly basis and more frequently with high-dose
therapy.
4. Use with caution in patients with third-space fluid collections such
as pleural effusion and ascites, as the half-life of methotrexate is prolonged,
leading to enhanced clinical toxicity. Fluid collections should
be drained before methotrexate therapy.
5. Use with caution in patients with bladder cancer status post cystectomy
and ileal conduit diversion as they are at increased risk for
delayed elimination of methotrexate and subsequent toxicity.
6. With high-dose therapy, methotrexate doses .1 grams/m2, important
to vigorously hydrate the patient with 2.5–3.5 liters/m2/day of IV
0.9% sodium chloride starting 12 hours before and for 24–48 hours
after methotrexate infusion. Sodium bicarbonate (1–2 amps/L solution)
should be included in the IV fluid to ensure that the urine pH
is greater than 7.0 at the time of drug infusion and ideally for up to
48–72 hours after drug is given.
7. Methotrexate blood levels should be monitored in patients receiving
high-dose therapy, patients with renal dysfunction (CrCl ,60 mL/min)
regardless of dose, and patients who have experienced excessive toxicity
with prior treatment with methotrexate.
8. With high-dose therapy, methotrexate blood levels should be monitored
every 24 hours starting at 24 hours after methotrexate infusion.
Rescue with leucovorin or L-leucovorin, the active isomer of
leucovorin, should begin at 24 hours after drug infusion and should
continue until the methotrexate drug level is ,50 nM.
9. Glucarpidase is indicated for the treatment of toxic plasma methotrexate
concentrations (.1 mM) in patients with delayed drug clearance
due to impaired renal function.
10. Patients should be instructed to lie on their side for at least 1 hour
after intrathecal administration of methotrexate. This will ensure
adequate delivery of drug throughout the CSF.
11. Intrathecal administration of methotrexate may lead to myelosuppression
and/or mucositis as therapeutic blood levels can be
achieved.
12. Methotrexate overdose can be treated with leucovorin, L-leucovorin,
and/or thymidine.
13. Instruct patients to avoid sun exposure for at least 1 month after therapy.
14. Caution patients about drinking carbonated beverages as they can
increase the acidity of urine, resulting in impaired drug elimination.
15. Pregnancy category D. Breastfeeding should be avoided.
Toxicity 1
Myelosuppression is dose-limiting toxicity with leukocyte nadir at days
4–7 and recovery usually by day 14.
Toxicity 2
Mucositis can be dose-limiting. Typical onset is 3–7 days after methotrexate
therapy and precedes the decrease in leukocyte and platelet count.
Nausea and vomiting are dose-dependent.
Toxicity 3
Acute renal failure, azotemia, urinary retention, and uric acid nephropathy.
Renal toxicity results from the intratubular precipitation of methotrexate
and its metabolites. Methotrexate itself may exert a direct toxic effect on the
renal tubules.
Toxicity 4
Transient elevation in serum transaminases and bilirubin are often
observed with high-dose therapy. May occur within the first 12–24 hours
after start of infusion and returns to normal within 10 days.
Toxicity 5
Poorly defined pneumonitis characterized by fever, cough, and interstitial
pulmonary infiltrates.
Toxicity 6
Acute chemical arachnoiditis with headaches, nuchal rigidity, seizures,
vomiting, fever, and an inflammatory cell infiltrate in the CSF observed immediately
after intrathecal administration. Chronic, demyelinating encephalopathy
observed in children months to years after intrathecal methotrexate and
presents as dementia, limb spasticity, and in advanced cases, coma.
Toxicity 7
Acute cerebral dysfunction with paresis, aphasia, behavioral abnormalities,
and seizures observed in 5%–15% of patients receiving high-dose
methotrexate. Usually occurs within 6 days of treatment and resolves within
48–72 hours. A chronic form of neurotoxicity manifested as an encephalopathy
with dementia and motor paresis can develop 2–4 months after
treatment.
Toxicity 8
Erythematous skin rash, pruritus, urticaria, photosensitivity, and hyperpigmentation.
Radiation-recall skin reaction is also observed.
Toxicity 9
Menstrual irregularities, abortion, and fetal deaths in women. Reversible
oligospermia with testicular failure reported in men with high-dose therapy.
SPECIFICATION
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