What can clinicians learn from therapeutic studies about the treatment of acute oral methotrexate poisoning?

CONTEXT: Methotrexate (MTX) is an anti-folate drug that has been utilized in both malignant and chronic inflammatory conditions. Doctors are often concerned with a potential adverse outcome when managing patients with acute oral MTX poisoning given its potential for serious adverse reactions at therapeutic doses. However, there is surprisingly little data from acute poisoning cases and more data from the therapeutic use of high-dose MTX.

OBJECTIVES: To review pharmacokinetic and pharmacological properties of MTX and systematically review series of acute MTX poisonings and therapeutic studies on high-dose MTX that provide pharmacokinetic or clinical data.

METHODS: An Embase (1974-October 2016) and Medline (1946-October 2016) search was performed by combining "MTX" and "overdose/poison" or "MTX" and "toxicity" or "MTX" and "high-dose MTX" or "MTX" and "bioavailability" or "pharmacokinetics"; 25, 135, 109 and 365 articles were found, respectively, after duplicates were removed. There were 15 papers that provided clinical data on acute ingestion and toxicity that occurred with low-dose administration. Eighteen papers were on high-dose MTX (>1 g per m2 body surface area) used as a single chemotherapy agent which provided pharmacokinetic or clinical data on MTX toxicity. Thirty papers were reviewed to determine the toxic dose, pharmacokinetics, risk factors, clinical symptoms and management of acute MTX toxicity. Given the limited acute poisoning data, a retrospective audit was performed through the consultant records of the New South Wales Poisons Information Centre from April 2004 to July 2015 to examine the clinical syndrome and toxicity of acute oral MTX poisoning. Pharmacokinetics: Reduced MTX bioavailability is a result of saturable absorption. Although maximal bioavailable absorption occurs at a dose of ∼15 mg m-2 , splitting the dose increases bioavailability. MTX clearance is proportional to renal function. Acute toxicity: Oncologists prescribe doses up to 12 g m-2 of MTX. Patients treated with an intravenous dose of MTX <1g m-2 do not require folinic acid rescue. MTX toxicity correlates better with duration and extent of exposure than peak serum concentration. Acute oral poisoning: Acute oral MTX poisoning in 177 patients did not report any severe toxicity. In the New South Wales Poisons Information Centre audit data (2004-2015), 51 cases of acute MTX poisoning were reported, of which 15 were accidental paediatric ingestions. The median reported paediatric ingestion was 50 mg (IQR: 10-100; range: 10-150) with a median age of 2 years (IQR: 2-2; range: 1-4). Of the 36 patients with acute deliberate MTX poisoning, median age and dose were 47 years (IQR: 31-62; range: 10-85) and 325 mg (IQR: 85-500; range: 40-1000), respectively. Of the 19 patients who had serum MTX concentrations measured, all were significantly below the concentrations used in oncology and the folinic acid rescue nomogram line and no patient reported adverse sequelae. Management of acute oral poisoning: Due to the low bioavailability of MTX, treatment is not necessary for single ingestions. Oral folinic acid may be used to lower the bioavailability further with large ingestions >1 g m-2 . Oral followed by intravenous folinic acid may be used in patients with staggered ingestion >36 h or patients with acute overdose and renal impairment (eGFR <45 mL/min/1.73 m2 ).

CONCLUSIONS: As a consequence of saturable absorption MTXs bioavailability is so low that neither accidental paediatric MTX ingestion nor acute deliberate MTX overdose causes toxicity. An acute oral overdose will not provide a bioavailable dose even close to 1 g m-2 of parenteral MTX. Hence, no treatment is required in acute ingestion unless the patient has renal failure or staggered ingestion. There is also no need to monitor MTX concentrations in acute oral MTX poisoning.