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Dichloromethotrexate (DCMTX) has been the subject of sporadic clinical development for the last 30 years. Although DCMTX was developed in hopes of discovering a more potent antifolate, the potential pharmacologic and toxicologic advantages of the analog have become of greater interest. This phase I and pharmacokinetic trial of DCMTX given on days 1, 8, and 15 every 28 days was undertaken to test these potential advantages. The maximally tolerated dose on this schedule was 980 mg/m2. Hepatic toxicity was dose limiting. Malaise, myelosuppression, and mucositis were also major toxic effects. The recommended dose for subsequent phase II studies of DCMTX administered on this schedule is 785 mg/m2 with a reduction to 625 mg/m2 for patients with a poor performance status or extensive prior therapy. Plasma disappearance curves for most patients were biphasic or triphasic, although several demonstrated more complex kinetic patterns that suggested significant enterohepatic circulation. The magnitude of the area under the plasma disappearance curve was related to the severity of DCMTX-induced hepatotoxicity. The elimination kinetics were linear, with a mean plasma clearance of 294 mL/min (range, 128-715). The pharmacokinetic behavior of DCMTX does not support its use over methotrexate in regional perfusion. DCMTX's primarily nonrenal elimination suggests that it may have an advantage over methotrexate when combined with nephrotoxic drugs such as cisplatin. However, there is little reason to commit major resources to further evaluation of DCMTX unless significant advantages in antineoplastic activity are identified.

Trimetrexate glucuronate (TMTX), a nonclassical folate antagonist, has been evaluated clinically on several schedules. We have studied TMTX administered as an iv bolus for 5 consecutive days every 3 weeks in 35 patients with advanced solid tumors. Drug was given at doses ranging from 7.6 to 18.8 mg/m2. The maximal tolerated dose was 13.1 mg/m2 per day x 5 for patients without prior myelotoxic treatment and 7.6 mg/m2 per day x 5 for previously treated patients. Because of wide individual differences in drug tolerance, dose escalation in 25% increments is recommended for patients not experiencing toxic effects. The dose-limiting toxicity was neutropenia. Rash and mucositis were also significant. TMTX concentrations were measured 1 and 24 hours after each dose, and the data were fit by use of a one-compartment pharmacokinetic model. With this simplified sampling and modeling scheme, the mean total body clearance (+/- SD) of trimetrexate was 31 +/- 20 mL/min per m2 and the volume of distribution was 13 +/- 7 L/m2. Mean plasma concentrations 1 hour after a dose were 1.12, 2.43, 3.33, and 3.25 mumol/L at 7.6, 9.1, 10.9, and 13.1 mg/m2, respectively. The mean TMTX concentration (+/- SD) 24 hours after a dose was 114 +/- 87 nmol/L. The mean area under the concentration-versus-time curve at 13.1 mg/m2 was 2,266 mumol.min/L. The drug concentration 1 hour after the first dose and the area under the concentration-versus-time curve were highly correlated with leukopenia and thrombocytopenia (r = .6 and .65 and P = .0007 and .0001, respectively). The maximal tolerated dose on the daily x 5 schedule was 30% of the dose tolerated on an iv bolus schedule. The choice of drug schedule for clinical trials when murine and human pharmacokinetics differ is discussed. Phase II trials are under way with both the iv bolus and the daily x 5 schedules.