A phase I trial of trimetrexate glucuronate (NSC 352122) given every 3 weeks: clinical pharmacology and pharmacodynamics

Summary

Trimetrexate glucuronate (TMTX), a non-classic folate antagonist, has been evaluated clinically on several schedules. We studied TMTX given as an i.v. bolus over 5–30 min every 3 weeks in 44 patients with advanced solid tumors; it was given at doses ranging from 20 to 275 mg/m². The maximal tolerated dose (MTD) on this schedule is 220 mg/m², which we also recommend as a starting dose for phase II studies in patients without extensive prior therapy. Because of wide individual differences in drug tolerance, dose escalation in 25% increments is recommended for non-toxic patients. The principal dose-limiting toxicity was myelosuppression, although in some patients a flu-like syndrome precluded dose escalation. Significant rash and mucositis also frequently occurred in toxic patients. TMTX plasma concentrations were measured after the first dose and the data were fit by two-or three-compartment mammillary pharmacokinetic models. The TMTX clearance rate was 36.5±21 ml/min per m² and did not change with dose; non-linearities with increasing dose were apparent in the steady-state volume of distribution (V_SS) and in the terminal disposition half-life (t 1/2). The difference between pre-treatment and nadir leucocyte counts was correlated with TMTX dose (r=0.58; P=0.0006) and with the area under the concentration vs time curve (AUC) (r=0.41; P=0.02). Pre-treatment plasma albumin concentrations correlated weakly with the nadir white blood count (r=-0.36; P=0.047). Optimal schedules for the administration of TMTX have not been established and phase II trials using both bolus and daily x5 schedules are under way.