TRIMETREXATE - A REVIEW OF ITS PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES AND THERAPEUTIC POTENTIAL IN THE TREATMENT OF PNEUMOCYSTIS-CARINII PNEUMONIA

Trimetrexate is a folinic acid analogue structurally related to methot rexate, whose primary mechanism of action is believed to be inhibition of dihydrofolate reductase. This reduces the production of DNA and RN A precursors and leads to cell death. Trimetrexate is lipophilic and c an passively diffuse across cell membranes including those of Pneumocy stis carinii and its mammalian host. To minimise toxicity, trimetrexat e must be coadministered with calcium folinate (leucovorin calcium), a reduced folate coenzyme, which is transported into, and protects, mam malian host cells but not P. carinii cells. In noncomparative trials t rimetrexate was effective in the treatment of P. carinii pneumonia (PC P) in patients with AIDS who were intolerant of or refractory to cotri moxazole (trimethoprim/sulfamethoxazole) and pentamidine treatment. In these patients, 2- to 4-week survival rates of 48 to 69% were reporte d. In a comparative trial in the initial therapy of PCP, trimetrexate was less effective than cotrimoxazole in moderate to severe disease as evidenced by a significantly higher failure rate. Trimetrexate was be tter tolerated than cotrimoxazole when used in this setting, however. Significantly fewer patients receiving trimetrexate plus calcium folin ate discontinued treatment because of adverse events than did patients receiving cotrimoxazole. The most common adverse effect associated wi th trimetrexate is myelosuppression (neutropenia and thrombocytopenia) ; this is mitigated by coadministration of calcium folinate and is gen erally reversible upon dosage reduction or discontinuation Other adver se effects include increases in serum aminotransferase levels, anaemia , fever rash/pruritus, and increased alkaline phosphatase or serum cre atinine levels. Further research into the use of trimetrexate, includi ng its efficacy as prophylaxis,, in combination with other agents and as an oral formulation, is needed to clearly define its role in the tr eatment of PCP and to identify patients most likely to benefit. Curren tly, trimetrexate should be considered as an alternative treatment opt ion in immunocompromised patients with moderate to severe PCP who have not responded to or are intolerant of first-line therapy