Link to Problems for discussion

Methotrexate


OVERVIEW


Methotrexate is a folic acid antagonist that may cause multiple organ damage when taken in overdose. Single acute oral ingestions often escape injury as the absorption of methotrexate is an active process which is saturated in overdose and therefore bioavailability falls with increasing doses. The antidote folinic acid (Leucovorin) should be given intravenously as soon as it is recognised that the patient has ingested methotrexate as its efficacy drops rapidly with time after overdose.

Methotrexate (MTX) is a widely used antineoplastic and immunosuppressive agent. Cellular toxicity following parenteral administration in the therapeutic setting is well described and, in fact, the desired effect. In this situation, ‘folinic acid rescue’ is used to limit toxicity. Acute oral overdose is relatively unusual but engenders great alarm because of the known toxicity associated with therapeutic use. However, cellular toxicity is as yet undescribed in this setting. The major unresolved issues in the management of acute oral overdose relate to whether there is a risk of cellular toxicity, what dose (if any) is required and what are the indications (if any) for administration of the specific antidote, folinic acid.

MECHANISM OF TOXIC EFFECTS


Methotrexate’s therapeutic and toxic effects are a result of its ability to limit DNA and RNA synthesis by inhibiting dihydrofolate reductase and thymidylate synthetase. It enters cells through an active transport system used by folate and binds to and inhibits the enzyme. This enzyme maintains reduced folate by recycling dihydrofolic acid which has been produced during thymidylate synthesis (see diagram). Dihydrofolate reductase reduces folic acid to tetrahydrofolate, an essential co-factor in the synthesis of purine nucleotides.

Mtx.jpg





Reduced folates are also required by thymidylate synthetase to provide methyl donors for the formation of thymidylate,
essential for DNA synthesis. Thus the effects of methotrexate poisoning are most apparent in more rapidly dividing cells such as gastrointestinal tract and bone marrow. Effects are also often observed on the liver as higher concentrations of methotrexate are provided to the liver through the portal circulation as the drug is absorbed. The antidote folinic acid supplies tetrahydrofolate and needs to be given for as long as the methotrexate is present in the cell (48-72 hours).

Acute renal failure can result from drug precipitation in the renal tubule, particularly in patients who are inadequately hydrated or not alkalinised.

Administration of reduced folate in the form of folinic acid (leucovorin) allows for continued purine synthesis in the methotrexate-toxic patient and is used in high-dose MTX therapy to limit the toxic effects.

KINETICS IN OVERDOSE


Absorption

Absorption of MTX after oral administration is saturable. Methotrexate is absorbed from the gastrointestinal tract via the active transport system which is used for folates. The bioavailability falls with increasing doses from > 50% to < 25% of the ingested dose. At doses less than 30 mg/m2, absorption is 90% whilst at doses greater than 80 mg/m2, absorption is less than 20%. It is for this reason that high-dose MTX therapy must be administered parenterally to achieve the desired plasma concentrations.This saturable absorption may protect against toxicity following acute oral overdose.

Distribution

The volume of distribution of methotrexate is about 0.6 L/kg. It is poorly lipid soluble and does not diffuse across lipid membranes. Its only method of entering cells is through active transport processes. It uses the folic acid transport systems and thus folic and folinic acid may compete for transport into cells as well as antagonising the effects inside cells. Methotrexate does not get transported into the CSF and CSF concentrations are generally < 5% of plasma concentrations. Once inside cells methotrexate is polyglutamated. The polyglutamation process inhibits the efflux of methotrexate from the cells. Polyglutamated methotrexate may be retained inside cells for up to 24 hours after serum methotrexate concentrations fall. The half life of methotrexate is 8-10 hours. However toxicity may continue for up to 24 hours after serum concentrations fall. This is due to the trapping of polyglutamated methotrexate inside cells.

Metabolism - Elimination

Methotrexate is eliminated almost entirely by renal excretion. MTX is predominantly excreted unchanged in the urine within 48 hours by both glomerular filtration and active tubular secretion. Toxicity is dependent more on the duration of concentration than dose administered.

Aspirin and probenecid inhibit methotrexate secretion in the proximal tubule and folinic acid blocks methotrexate reabsorption thus aspirin may increase toxicity and folinic acid may accelerate methotrexate excretion. The clearance of methotrexate is largely independent of urine flow rate.

CLINICAL EFFECTS


Clinical features of MTX toxicity are predominantly GI and neurological.

Gastrointestinal effects

The earliest effects are on the gastrointestinal tract with mucositis, stomatitis, nausea, vomiting and diarrhoea. These may still be delayed by some days in some patients.

Haematological effects

This occurs with a lag of 7-10 days and leukopenia and thrombocytopenia from methotrexate poisoning may be profound. These usually recover within 2 weeks when methotrexate is used in therapeutic doses but recovery may be further delayed in overdoses. Pancytopenia can occur within 2 weeks.

Hepatic effects

A rise in transaminases is very frequently observed. This acute hepatitis does not lead to chronic cirrhosis (c.f. hepatic fibrosis associated with chronic methotrexate poisoning). Hepatitis is not usually clinically severe.

Renal effects

Renal failure occurs and may be due to precipitation of methotrexate in the renal tubules. This occurs with high renal concentrations, particularly at acidic urine pH. Thus maintenance of good urine output and mild alkalinisation of the urine is recommended.

Central nervous system effects

Neurotoxicity is not expected with oral ingestions of methotrexate as methotrexate is water soluble and crosses the blood brain barrier poorly. A number of neurotoxic reactions have occurred with intrathecal methotrexate.
Neurological features are seizures and acute focal neurological dysfunction.

Other effects

Pneumonitis has been reported with chronic methotrexate use but not with acute overdose. Rashes are frequently reported in acute overdose. Methotrexate is embryotoxic and teratogenic.

RISK ASSESSMENT


MTX toxicity has not been described following acute oral overdose. Patients who ingest more than 500 mg in adults or more than 5 mg/kg in children should be referred for further assessment.

Acute ingestions by adults of greater than 500 mg are extremely unusual, as this is the dose contained in one full bottle. Similarly, accidental paediatric ingestion of more than 20-30 mg is rare. Parenteral MTX doses of less than 2 mg/kg are not usually associated with toxicity and is likely that the poor bioavailabily following oral administration, especially following overdose, affords greater protection.

Plasma MTX is predictive of risk of toxicity and a nomogram is used to guide the need for folinic acid rescue following high-dose parenteral therapy. Concentrations greater than 10 micromole/L at 0 hours, 5 micromole/L at 6 hours or 1 micromole/L at 12 hours indicate a risk of toxicity.

INVESTIGATIONS


Blood concentrations

Conversion factor
  • mg/L x 2.20 = micromol/L
  • micromol/L x 0.455 = mg/L

Plasma concentrations of methotrexate may be useful in confirming exposure and are performed in many oncology units. Concentrations less than 5 x 10-8 M have few adverse effects. Concentrations > 5 x 10-7 M at 48 hours or 5 x 10-6 M at 24 hours indicate a high risk of toxicity. Treatment should be commenced without awaiting concentrations.

Other investigations

All patients should have a baseline full blood count, electrolytes, LFTs and these may need to be monitored for 2 weeks.

TREATMENT


Supportive

Where a low-dose ingestion can be confirmed on history, the patient is asymptomatic and there have been no significant co-ingestions, specific management is unlikely to be required.

Patients with clinically significant methotrexate poisoning and in particular myelosuppression should be managed by a specialist oncology or haematology unit. They may require:
  • barrier nursing
  • prophylactic antibiotics
  • antiemetics
  • mouth care
  • transfusions
  • G-CSF or GM-CSF
  • bone marrow transplant

The care is essentially similar to that for any patient who has had severe adverse effects from chemotherapy.

GI Decontamination

Activated charcoal should be given to oral ingestions who present within 1-2 hours.

Urine alkalinisation

Adequate fluids and mild urinary alkalinisation should be given to prevent renal failure.

Antidotes

At higher doses (especially more than 500 mg in adults or more than 5 mg/kg in children), then empiric folinic acid therapy may be considered but the precise indications are not established. Where doubt exists and a plasma MTX concentration result can be obtained within 24 hours of the ingestion, it is reasonable to base treatment decisions on this result. Where folinic acid therapy is delayed, clinical follow-up with a full blood examination at 7-10 days is prudent.

Folinic Acid (Leucovorin)
Folinic acid bypasses the block in the folic acid cycle. The time to treatment is very important in the efficacy of leucovorin. It should be given intravenously for the first dose and should be commenced as soon as the diagnosis has been made.

Dose
The dose of folinic acid is controversial. It has been suggested that the dose required varies with the dose of methotrexate. This may be due to the fact that folinic acid competes with methotrexate for uptake into cells. For this reason the first dose of folinic acid should be at least equal to the dose of methotrexate ingested (in mg). The dose of folinic acid should be repeated 4-6 hourly and continued for 48-72 hours. Dosage regimens based on methotrexate drug concentrations have been developed.

Methotrexate drug concentration (M)
Folinic Acid Dose (mg/M²)
  • 5 x 10-5
1000 every 6 hour IV
5 x 10-5 - 5 x 10-6
100 every 3 hour IV
5 x 10-6 - 5 x 10-7
30 every 6 hour or 10 every 3 hour IV, IM or oral
< 5 x 10-7
10 every 6 hour orally until plasma methotrexate is < 5 x 10-8 M

In practice oral ingestions do not acheive these levels ( either acutely or chronic). For chronic repeated ingestion or acute high ingestions folinic acid 15 mgs four times a day is sufficient.

Folic acid is not an antagonist for methotrexate poisoning. Large doses of oral folic acid might inhibit absorption of methotrexate and will compete for the intracellular transport. For large acute ingestions there is no reason to prefer folic acid over activated charcoal (apart from taste), for patients who are post absorption folic acid can reduce intra cellular transport.

Example of a nomogram for pharmacokinetically guided leucovorin rescue after high-dose methotrexate(MTX) administration. Adapted from Bleyer WA. Therapeutic drug monitoring of methotrexate and other antineoplastic drugs. In: Baer DM, Dita WR, eds. Interpretations in Therapeutic Drug Monitoring. Chicago: American Society of Clinical Pathology, 1981:169–181. ©1981 American Society of Clinical Pathologists.
Example of a nomogram for pharmacokinetically guided leucovorin rescue after high-dose methotrexate(MTX) administration. Adapted from Bleyer WA. Therapeutic drug monitoring of methotrexate and other antineoplastic drugs. In: Baer DM, Dita WR, eds. Interpretations in Therapeutic Drug Monitoring. Chicago: American Society of Clinical Pathology, 1981:169–181. ©1981 American Society of Clinical Pathologists.


Example of a nomogram for pharmacokinetically guided leucovorin rescue after high-dose methotrexate(MTX) administration. Adapted from Bleyer WA. Therapeutic drug monitoring of methotrexate and other antineoplastic drugs. In: Baer DM, Dita WR, eds. Interpretations in Therapeutic Drug Monitoring. Chicago: American Society of Clinical Pathology, 1981:169–181. ©1981 American Society of Clinical Pathologists.

Elimination enhancement

Haemodialysis
These may significantly increase clearance of methotrexate only in patients who have renal failure. Otherwise the half life with these treatments is similar to that which occurs without haemodialysis. The best evidence is for charcoal haemoperfusion.
Although urinary alkalinisation and haemodialysis enhance the elimination of MTX, these techniques have never been used for management of oral overdose.

LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP


No long term adverse effects have been reported from acute methotrexate poisoning. The prognosis is surprisingly favourable presumably due to the reduced bioavailability in overdose and the widespread availability of an effective antidote.

REFERENCES


Brigitte C. Widemanna, Peter C. Adamson b. Understanding and Managing Methotrexate Nephrotoxicity Pediatric Oncology 2006;11;694-703 (full text)
Thomas LL, Mertens MJ, von dem Borne AE, van Boxtel CJ, Veenhof CH, Veies EP. Clinical management of cytotoxic drug overdose. Med Toxicol Adverse Drug Exp 1988 Jul-Aug;3(4):253-63
West SG. Methotrexate hepatotoxicity. Rheum Dis Clin North Am 1997 Nov;23(4):883-915