Trimetrexate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of Pneumocystis carinii pneumonia

Abstract

Trimetrexate is a folinic acid analogue structurally related to methotrexate, whose primary mechanism of action is believed to be inhibition of dihydrofolate reductase. This reduces the production of DNA and RNA precursors and leads to cell death. Trimetrexate is lipophilic and can passively diffuse across cell membranes including those of Pneumocystis carinii and its mammalian host. To minimise toxicity, trimetrexate must be coadministered with calcium folinate (leucovorin calcium), a reduced folate coenzyme, which is transported into, and protects, mammalian host cells but not P. carinii cells. In noncomparative trials trimetrexate was effective in the treatment of P. carinii pneumonia (PCP) in patients with AIDS who were intolerant of or refractory to cotrimoxazole (trimethoprim/sulfamethoxazole) and pentamidine treatment. In these patients, 2- to 4-week survival rates of 48 to 69% were reported. 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 better tolerated than cotrimoxazole when used in this setting, however. Significantly fewer patients receiving trimetrexate plus calcium folinate discontinued treatment because of adverse events than did patients receiving cotrimoxazole. The most common adverse effect associated with trimetrexate is myelosuppression (neutropenia and thrombocytopenia); this is mitigated by coadministration of calcium folinate and is generally reversible upon dosage reduction or discontinuation. Other adverse effects include increases in serum aminotransferase levels, anaemia, fever, rash/pruritus, and increased alkaline phosphatase or serum creatinine levels. Further research into the use of trimetrexate, including its efficacy as prophylaxis, in combination with other agents and as an oral formulation, is needed to clearly define its role in the treatment of PCP and to identify patients most likely to benefit. Currently, trimetrexate should be considered as an alternative treatment option in immunocompromised patients with moderate to severe PCP who have not responded to or are intolerant of first-line therapy.