Trimetrexate

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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. Trimetrexate is a folate antagonist structurally related to methotrexate but distinguished by its lipophilic properties which allow it to enter cells independently of the folate membrane transport system. Mammalian cells have this transport system but Pneumocystis carinii does not. Thus, trimetrexate can enter P. carinii cells while hydrophillic compounds such as calcium folinate (leucovorin calcium) cannot. The mechanism of action of trimetrexate has not been fully elucidated; however, it is believed to be primarily due to inhibition of dihydrofolate reductase (DHFR). This inhibition reduces production of thymidylate and purines (DNA and RNA precursors) and leads to cell death. Host cells are protected from the cytotoxicity of trimetrexate by administration of calcium folinate, which is a fully reduced folate that enters the cell via the folate membrane transport system and can be directly utilised in cellular metabolism. In vitro, trimetrexate showed greater binding affinity for P. carinii DHFR and was more effective than trimethoprim or pyrimethamine in inhibiting P. carinii DHFR activity. Trimetrexate was less effective than sulfamethoxazole or pentamidine but more so than trimethoprim in its ability to inhibit incorporation of para-aminobenzoic acid by P. carinii in the de novo synthesis of reduced folates. Trimetrexate has also been shown to inhibit P. carinii cultured with human embryonic lung fibroblast cells and in immunosuppressed rodent models of P. carinii pneumonia (PCP). The majority of pharmacokinetic data with trimetrexate were obtained from patients being treated for cancer although limited studies have been performed in patients with AIDS receiving treatment for PCP. Most pharmacokinetic parameters are relatively consistent between patient populations and treatment regimens although there tends to be wide interpatient variability. After oral administration the mean bioavailability of trimetrexate is 44% with peak plasma concentrations achieved within 0.5 to 4 hours. Following intravenous administration there is a linear relationship between trimetrexate dose, and area under the plasma concentration-time curve and steady-state plasma concentrations. Distribution into other compartments is not well described, although data from a small number of patients have shown that trimetrexate distributes well into the respiratory tract but very poorly into the CNS. The primary route of elimination appears to be via hepatic metabolism (via cytochrome P450), as less than one-third of the drug is excreted unchanged in the urine. Trimetrexate is transformed to at least 2 metabolites, both of which inhibit DHFR. The elimination curve of trimetrexate is best described by either a biexponential or triexponential model with the elimination half-life reported to range from 4 to 12 hours in patients with AIDS and PCP and from 8 to 26 hours in patients with cancer. Noncomparative trials [including the large (n = 577) Treatment IND program] using trimetrexate as salvage therapy in patients with AIDS and PCP who were refractory to or intolerant of cotrimoxazole (trimethoprim/sulfamethoxazole) and pentamidine, reported 2- to 4-week survival rates ranging from 48 to 69%. Response rates ranged from 42 to 90% when assessed in patients with a variety of disease and treatment histories. In a randomised comparison with cotrimoxazole, trimetrexate (as initial therapy) was less effective but better tolerated. Treatment with trimetrexate resulted in a significantly higher failure rate (38 vs 20% at day 21) compared with cotrimoxazole. However, because discontinuation due to serious adverse effects was significantly more common in the cotrimoxazole group (see tolerability summary for details), the number of patients receiving their assigned treatment at the end of the 3-week study was similar in both groups. In patients with cancer, the main dose-limiting adverse effect of trimetrexate is myelosuppression, particularly neutropenia and thrombocytopenia. In these patients in whom concomitant calcium folinate is not used, there is a linear relationship between plasma trimetrexate concentration and haematological toxicity. This haematological toxicity is usually readily reversible upon dosage reduction or discontinuation. In patients with PCP, myelosuppression can be prevented or minimised by concurrent administration of calcium folinate. Other adverse effects include elevated serum aminotransferase levels, anaemia, fever, rash/pruritus and increased alkaline phosphatase or serum creatinine levels. Trimetrexate plus calcium folinate is better tolerated than cotrimoxazole when used in patients with AIDS for the initial treatment of PCP. In a comparative trial, discontinuation rates at day 21 due to adverse effects were 28% in patients treated with cotrimoxazole compared with 8% in patients treated with trimetrexate. In the treatment of immunocompromised patients with moderate to severe PCP, the recommended dosage of trimetrexate is 45 mg/m2/day infused intravenously over 60 to 90 minutes for 21 days. Calcium folinate 80 mg/m2/day, either orally or intravenously in 4 divided doses, must be used concomitantly and continued for 3 days beyond the completion of trimetrexate treatment. Dosage adjustments of both drugs may be required to limit neutropenia and thrombocytopenia.