Trimetrexate

Class:

Trimetrexate is a quinazolinediamine congener of methotrexate.

Antiparasitic Activity:

Trimetrexate is a potent competitive inhibitor of bacterial, protozoan, and mammalian dihydrofolate reductase.

Mechanism of Action:

Trimetrexate acts by inhibition of dihydrofolate reductase.

Mechanism of Resistance:

Resistance occurs through multiple mutations in the gene coding for this enzyme

Pharmacodynamics:

Trimetrexate concentrations between 3 and 54.1 ÁM inhibit the growth of trophozoites of Pneumocystis carinii

Pharmacokinetics:

The elimination half life of trimetrexate is about 11.4 hours and is usually administered intravenously. Plasma protein binding is reported to be > 95% but there is evidence of saturation at higher concentrations.

Dosage:

Sterile lyophilized powder in single-dose vials of 25mg.

P. carinii pneumonia: trimetrexate 45 mg/m2 daily, plus folinic acid 80 mg/m2.

Disease state based dosing:

Interruption of trimetrexate is advisable if serum creatinine concentrations increase to > 2.5 mg/dL. Transient elevations of transaminases and alkaline phosphatase been observed in patients treated with Neutrexin. Interruption of treatment is advisable if transaminase levels or alkaline phosphatase levels increase to >5 times the upper limit of normal range.

Adverse Effects:

Adverse effects include increases in serum aminotransferase levels, anaemia, fever and rash. In cerebral toxoplasmosis the most common adverse effect is myelosuppression, which can be reduced by co-administration of folinic acid.

Contraindications:

Trimetrexate glucuronate is contraindicated in patients with clinically significant sensitivity to trimetrexate, leucovorin, or methotrexate.

Drug Interactions:

Since trimetrexate is metabolized by cytochromes P450, drugs that induce or inhibit this drug metabolizing enzyme system could elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be co-administered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole

Pregnancy:

Neutrexin can cause fetal harm when administered to pregnant women. If Neutrexin is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Brand names/Manufacturer:

Neutrexin (Ben Venue Laboratories, Inc.)