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Information about Trimetrexate

Trimetrexate is a parenterally administered folate antagonist that is used as a second line therapy for severe Pneumocystis jirovecii (previously carinii) pneumonia.

Liver safety of Trimetrexate

Trimetrexate therapy has been associated with transient, mild serum enzyme elevations during therapy, but has not been convincingly linked to instances of acute, clinically apparent liver injury.

Mechanism of action of Trimetrexate

Trimetrexate (trye" me trex' ate) is a folic acid analogue which acts as an antagonist inhibiting the enzymes involved in folate dependent synthetic pathways such as thymidine synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. Inhibition of these enzymes leads to decrease in intracellular thymidine and purine which interferes with RNA and DNA synthesis and leads to apoptotic cell death in rapidly dividing cells. Trimetrexate is a nonclassical folate antagonist and, unlike methotrexate, is lipid soluble which leads to different pharmacokinetics and tissue distribution. Trimetrexate was developed as an antineoplastic agent and showed some activity against breast, lung and head and neck cancer, but had difficult toxicities and never received approval for these uses in the United States. Trimetrexate is also taken up by pathogens including Pneumocystis jirovecii where it blocks the folate dependent synthetic pathways and causes their death. At the same time, folate being water soluble can partially block the systemic effects of trimetrexate, but is not taken up by the pathogens. For this reason, high doses of trimetrexate combined with leucovorin “rescue” were evaluated as therapy of Pneumocystis jirovecii in patients who were resistant or intolerant of first line anti-Pneumocystis therapies. Trimetrexate was approved for use as a second line therapy of moderate-to-severe Pneumocystis jirovecii pneumonia in immunodeficient patients in the United States in 1993. It remains available as a second line drug for this indication, but has not been widely used.

Dosage and administration for Trimetrexate

Trimetrexate is available in single use vials of 25 or 200 mg as a powder for reconstitution under the brand name Neutrexin. The recommended dose is 45 mg/m2 once daily for 21 days concurrent with leucovorin, orally or intravenously, four times daily for 24 days.

Side effects of Trimetrexate

When given with leucovorin, trimetrexate is well tolerated, but can cause many of the ceommon side effects of other folate antagonists such as fatigue, nausea, vomiting, anorexia, diarrhea, alopecia, anemia, neutropenia and rash. Uncommon, but potentially serious adverse events include febrile neutropenia, infections, dehydration, renal failure, arrhythmias and peripheral neuropathy.

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