Low dose methotrexate: Risk factors for acute toxicity

Last updated: February 27, 2020

Risk factors for developing acute toxicity with low dose methotrexate include:

Renal failure
Methotrexate is predominantly excreted unchanged in the urine; it is filtered in the renal glomeruli and also undergoes active secretion and reabsorption in the renal tubules. Worsening renal function is associated with increasing toxicity including death due to myelosuppression.

Intercurrent illness
The presence of conditions that cause dehydration (e.g. diarrhoea, vomiting, fever) can cause toxicity because of the potential, subsequent impact on renal function.

Interacting medicines
Concomitant medicines may increase the risk of acute methotrexate toxicity as a result of various pharmacokinetic and pharmacodynamic interactions. These include:
✦  Decreased renal excretion of methotrexate (e.g. NSAIDs, salicylates, probenecid, some penicillins)
✦  Displacement of methotrexate bound to plasma protein resulting in more ‘free’ (unbound) drug (e.g. NSAIDs, salicylates)
✦  Additive side effects such as with drugs that cause hepatotoxicity (e.g. alcohol) and those that have the potential to cause myelosuppression (e.g. co-trimoxazole, trimethoprim)

Around one half of circulating methotrexate is bound to plasma protein. Low albumin levels may result in more ‘free’ (unbound) methotrexate in the plasma and tissues. The unbound fraction is responsible for the pharmacological activity of the drug and its potential toxicity. However, only the unbound fraction can be cleared by the kidneys.

Advancing age
Increasing age appears to be a risk factor for developing acute toxicity with low dose methotrexate, in part due to changes in the distribution, metabolism and excretion of the drug. The decrease in lean body mass, hepatic metabolism and renal excretion associated with ageing may all lead to methotrexate toxicity. Folate reserves also decrease with advancing age, increasing the risk of toxicity.

    Li is 65 years old and advancing age is a risk factor for developing acute toxicity with low dose methotrexate. Although ageing is associated with reduced plasma albumin levels, Li’s is within range.

He also has a history of chronic kidney disease; analysis of multiple trials in patients with rheumatoid arthritis indicate that baseline renal function is a predictor of methotrexate toxicity. Worsening renal function is associated with an increased risk of toxicity. The presence of fever may impact upon his kidney function further if acute dehydration occurs.

Li’s prescription for amoxicillin may also have contributed to methotrexate toxicity. Penicillins including amoxicillin have been reported to interact with low dose methotrexate. Serious interactions are rare but fatalities have been reported.
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