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Methotrexate


OVERVIEW


Methotrexate is a folic acid antagonist. There are two common patterns of exposure, one is inadvertent daily dosing from therapeutic error and the other is deliberate or accidental acute ingestions. Single acute oral ingestions often escape injury as the absorption of methotrexate is an active process which is saturable in overdose and therefore bioavailability falls with increasing doses. Methotrexate clearance is proportional to renal function. The antidote folinic acid (Leucovorin) may be used in large ingestion or renal failure to compete with absorption as they share the same transporter. Folinic acid may also be given intravenously for acute ingestions if patients have severe renal failure or chronic methotrexate toxicities.

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, methotrexate toxicity is more dependent on duration of exposure rather than serum concentration. Apart from severe renal failure particularly dialysis dependent patients, there were no case series that demonstrate severe methotrexate toxicities in acute poisoning. On the other hand, severe toxicities and deaths were reported with inadvertent daily dosing of methotreate for as few as 3-7 days.

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 folinic acid 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.

Methotrexate mechanism simple.jpg
Simple methotrexate diagram




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 MTX 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 folinic acid transport systems and thus 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 between 1 to 4 weeks after serum methotrexate concentrations fall. The distribution half life is 2 hours while elimination half life of methotrexate is 8-10 hours. However toxicity may continue 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. Renal failure reduces MTX clearance and increases the duration of exposure to MTX.

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. see methotrexate pathway pharmacokinetics

CLINICAL EFFECTS


Clinical features of MTX toxicity are predominantly gastrointestinal, haematological and renal.

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


Apart from severe renal failure patients, severe MTX toxicity has not been described following acute oral overdose. Patients with dehydration, renal impairment, large ingestions (>500 mg in adults or >2 mg/kg in children) or inadvertent daily dosing should all be referred for assessment and management.

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 1 g/m2 are not treated by oncologists with folinic acid. There is no feasible acute oral overdoses that is likely to provide a bioavailable dose even close to 1 g/m2. It is likely that the poor bioavailability following oral administration, especially following overdose, affords greater protection.

Following high dose parenteral MTX therapy, plasma MTX is predictive of risk of toxicity and a nomogram is used to guide the need for folinic acid rescue. Concentrations greater than 10 micromole/L at 24 hours, >0.1 micromole/L at or above 48 hours indicate a need for folinic acid rescue.

INVESTIGATIONS


Blood concentrations

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

Monitoring of plasma concentrations of MTX are not helpful in either acute or chronic ingestions because of the low bioavailability, rapid intracellular uptake coupled with its short distribution half life. However, in the oncology data in which intermediate or high dose MTX (1 - 33 g/m2) are used, concentrations >10uM at 24 hours or >1 uM at 48 hours and >0.1 uM at 72 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 with normal renal function 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

Due to saturable bioavailability, decontamination with Activated charcoal is unlikely to be useful in acute ingestion.

Urine alkalinisation

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

Antidotes

In patients with renal failure or large ingestion (especially more than 500 mg in adults or more than 5 mg/kg in children), it is reasonable to give oral folinic acid (15 mg) to compete for absorption as it is inexpensive, easily administered and completely safe. Repeated intravenous doses of folinic acid (15 mg Q6h) may be considered in patients with renal failure or chronic MTX poisonings.

Folinic Acid (Leucovorin)
Folinic acid has two antidotal actions. It interferes with absorption and transport of MTX and it also bypasses the block in the folic acid cycle. The time to treatment is very important in the efficacy of leucovorin. It can be given orally to compete with absorption in patients with large acute ingestion or renal failure. Repeated doses of folinic acid may be given to patients with renal failure having taken an acute ingestion or chronic MTX poisonings.

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. However, folinic acid has saturable bioavailability and its absorption is maximal at 15 mg. For this reason the first dose of folinic acid should be at least 15 mg and should be started as soon as possible. The optimal dose of IV folinic acid is not known but it is unlikely to be greater than 10 mg/m2 for 48-72 hrs or until clinical recovery in chronic poisonings. This is because the serum concentration will be below the folinic acid rescue line. Dosage regimens based on methotrexate drug concentrations have been developed.

Methotrexate drug concentration (uM)
Folinic Acid Dose (mg/M²)
50
1000 every 6 hour IV
5 - 50
100 every 3 hour IV
0.5 - 5
30 every 6 hour or 10 every 3 hour IV, IM or oral
< 0.5
10 every 6 hour orally until plasma methotrexate is 0.05 uM

Folic acid is not an antagonist for methotrexate poisoning. Concomitant administration of folate with MTX did not have a significant effect on the bioavailability of MTX, suggesting that folate may have a separate transporter from that of MTX

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 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